Ebook Oncology in primary care: Part 2

(BQ) Part 2 book “Oncology in primary care” hass contents: Bone health, hepatocellular carcinoma, prostate cancer, bladder cancer, kidney cancer, breast cancer, gynecologic cancers, psychosocial sequelae of cancer, sexual dysfunction,… and other contents.

Trang 1

Cancer Survivorship

Trang 2

CHAPTER

Kevin C Oeffinger, MD

Cancer Survivors, Oncologists, and Primary Care Clinicians 38

KEY POINTS

• The population of cancer survivors is growing rapidly;

many cancer survivors have complex health care needs.

• Risk-based health care of cancer survivors is lifelong care

that integrates the cancer and survivorship experience

in the overall health care needs of the individual and

includes a systematic plan for surveillance and prevention

that incorporates risks based on the previous cancer,

cancer therapy, genetic factors, lifestyle behaviors, and

comorbid health conditions.

• The survivorship care plan is a key component of

risk-based health care.

• Many cancer survivors are lost in transition from active

therapy to posttreatment health care and have many

health care needs that are not addressed.

• The primary care clinician’s role in the care of cancer

survivors is critically important.

strategies that incorporate prevention and early detection

The Institute of Medicine (IOM) published two seminal reports on survivors of childhood and adult cancer.2,7 The latter report, subtitled Lost in Transition, highlighted the

fact that the transition of patients from active cancer therapy

to posttreatment care is often suboptimal.2 Through these reports, the concept of risk-based health care for cancer sur-vivors was developed Risk-based health care (Table 38-1)

is an approach to lifelong care that integrates the cancer and survivorship experience in the overall health care needs of the individual and includes a systematic plan for surveillance and prevention that incorporates risks based on the previ-ous cancer, cancer therapy, genetic factors, lifestyle behav-iors, and comorbid health conditions The document that is the cornerstone of this process is the survivorship care plan (SCP), which includes an individualized cancer treatment summary, information on potential late effects, and guide-lines for follow-up care Figure 38-1 provides an example

• Longitudinal care that is considered a continuum from cancer diagnosis to eventual death regardless of age

• Continuity of care consisting of a partnership between the survivor and a health care provider who can coordinate necessary services

• Comprehensive, anticipatory, personalized, and proactive care that includes a systematic plan of prevention and surveillance

• Multidisciplinary team approach with communication between the primary health care provider, cancer specialists, and allied/ancillary service providers

• Health care of the whole person, not a specifi c disease or organ system, which includes the individual’s family and his or her cultural and spiritual values

• Sensitivity to the issues of the cancer experience, including expressed and unexpressed fears of the survivor and his or her family/spouse

TABLE 38-1 Basic Tenets of Risk-Based Health

Care of Cancer Survivors

Long-term cancer survivors represent a signifi cant proportion

of the US population Currently, there are more than 12

mil-lion cancer survivors; by 2020, it is estimated that this

num-ber will increase to 20 million.1 As the number of long-term

survivors has increased, there has been a growing

realiza-tion that many will develop health condirealiza-tions as a direct or

an indirect consequence of their cancer therapy.2–6 Although

some of these conditions occur during therapy and persist well

after the therapy has been completed (or become permanent),

such as ifosfamide-induced renal dysfunction or

steroid-induced osteonecrosis, many outcomes are not evident until

10 to 20 years later such as second cancers and therapy-related

heart failure or ischemic coronary artery disease Collectively,

these outcomes are referred to as “late effects.”

Fortunately, the incidence and severity of many late

effects of cancer therapy can be substantially reduced with

Trang 3

Ch a p t e r 3 8 / C a n c e r S u r v i v o r s , O n c o l o g i s t s , a n d P r i m a r y C a re C l i n i c i a n s 239

CANCER TREATMENT SUMMARY / SURVIVORSHIP CARE PLAN

Date of preparation: June 14, 2012

Cancer Diagnosis: Hodgkin lymphoma, nodular sclerosing, stage IV B

Treatment center: Best Cancer Center, USA

Date of diagnosis: 12/1/1998 Age at diagnosis: 26 y

Date of completion of therapy: 7/29/1999

Surgery

Radiation Therapy

6/1/1999 6/24/1999 Modified mantle (cervical, supraclavicular, infraclavicular,

mediastinal, and left axillary nodes)

• EKG baseline and as clinically indicated

• Breast MRI/mammogram annually

• DXA baseline and as clinically indicated

• Pulmonary function test baseline and as clinically indicated

• Annual blood work: CBC, BUN, creatinine, fasting lipids, TSH, urinalysis

• Counseling as needed

• Yearly evaluation of skin in radiation field

**Screening recommendations adapted from the Children’s Oncology Group Long-Term Follow-Up Guidelines

http://www.survivorshipguidelines.org

For any questions, please contact:

Dr Mary Doe

Best Cancer Center, Anywhere USA

1111 Main Street, USA

Trang 4

240 O n c o l o g y i n P r i m a r y C a re

Low risk for future cancer-related

health problems:

All of the following:

• Surgery only or chemotherapy that

did not include alkylating agent,

anthracycline, bleomycin, or

epipodophyllotoxin

• No radiation

• Low risk of recurrence

• Mild or no persistent toxicity of

therapy

Moderate risk:

Any of the following:

• Low- or moderate-dose alkylating

agent, anthracycline, bleomycin,

or epipodophyllotoxin

• Low-to-moderate dose radiation

• Autologous stem cell transplant

• Moderate risk of recurrence

• Moderate persistent toxicity of

• Allogeneic stem cell transplant

• High risk of recurrence

• Multi-organ persistent toxicity of

therapy

Communication points with PCC

a CA DX and planned therapeutic approach, brief overview of chemotherapy, radiation therapy, and/or surgery

b Survivorship care plan: CA DX, cancer therapy, surveillance recommendations, contact information

c Periodic update with changes in surveillance recommendations and new information regarding potential late effects

d Periodic update of survivor’s health for PCC record

FIGURE 38-2. Risk-stratifi ed shared care model for cancer survivors Solid line denotes primary responsibility for cancer-related care; PCC continues care to manage

non-cancer comorbidities and routine preventive health maintenance *Cancer center or oncologist/oncology group practice; if there is not an LTFU/survivor program available,

care in the gray box is provided by the primary oncologist CA, cancer; DX, diagnosis; Off RX, completion of cancer therapy; PCC, primary care clinician; LTFU, long-term

follow-up (survivor) program; Onc, oncologist.

Trang 5

Ch a p t e r 3 8 / C a n c e r S u r v i v o r s , O n c o l o g i s t s , a n d P r i m a r y C a re C l i n i c i a n s 241

of a simple one-page SCP Despite recommendations from

the IOM and numerous other national groups, studies

indi-cate that most survivors do not have an SCP; they are often

unsure about the details of their cancer therapies; and most

community physicians are unaware of their risks Thus, most

survivors, including those at highest risk, are not engaged in

risk-based follow-up care that is aimed on optimizing their

health and quality of life

The following chapters highlight some of the more ous late effects and key aspects of integrating the health care needs of the cancer survivor with his or her routine health care needs The primary care clinician, with expertise in preventive care and the management of chronic conditions, is critically important in this process Figure 38-2 presents an approach, stratifi ed by risk, for shared care between the primary care clinician and the cancer specialist(s)

seri-References

1 Parry C, Kent EE, Mariotto AB, et al Cancer survivors: a booming

popu-lation Cancer Epidemiol Biomarkers Prev 2011;20(10):1996–2005.

2 Hewitt M, Greenfi eld S, Stovall E, eds From Cancer Patient to Cancer

Survivor: Lost in Transition Washington, DC: Committee on Cancer

Survivorship: Improving Care and Quality of Life, National Cancer Policy

Board, Institute of Medicine, and National Research Council, National

Academies Press; 2006.

3 Ganz PA Why and how to study the fate of cancer survivors: observations

from the clinic and the research laboratory Eur J Cancer 2003;39(15):

2136–2141.

4 Oeffi nger KC, Robison LL Childhood cancer survivors, late effects, and a

new model for understanding survivorship JAMA 2007;297(24):2762–2764.

5 Bhatia S, Robison LL Cancer survivorship research: opportunities

and future needs for expanding the research base Cancer Epidemiol Biomarkers Prev 2008;17(7):1551–1557.

6 Oeffi nger KC, McCabe MS Models for delivering survivorship care

Trang 6

CHAPTER

KEY POINTS

• Cardiac and pulmonary sequelae are major contributing

factors to serious morbidity and premature mortality

among survivors of cancer.

• Chest (mediastinal) radiation frequently causes ischemic

coronary artery disease Traditional risk factors increase

this risk and therefore should be aggressively managed.

• Anthracycline therapy frequently causes asymptomatic

left ventricular dysfunction, which occasionally can

progress to overt heart failure.

• Pulmonary disease including pulmonary fi brosis and

restrictive and obstructive lung disease can result from

radiation to the chest and/or bleomycin and other

pulmonary toxic chemotherapeutic agents.

Jennifer E Liu, MD, FACC • Kevin C Oeffinger, MD39

increase risk Alternatively, indirect multifactorial pathways may lead to CAD Lastly, patients with cancer often are disconnected from their primary care provider as they are treated for their can-cer and followed for recurrence This can result in suboptimal management of traditional cardiovascular risk factors, such as diabetes and hypertension, hastening the development of CAD

Ischemic Coronary Artery DiseaseRadiation fi elds that include the mediastinum, often used in the therapy of Hodgkin and non-Hodgkin lymphoma, can cause direct injury to the proximal coronary arteries and accelerate atherosclerotic plaque formation leading to CAD (Fig 39-2) and myocardial infarction (MI)

Following mediastinal radiation:

• By 20 years, the cumulative incidence of symptomatic CAD is 21%.12

• By 30 years, the cumulative incidence of MI is 13%.1

• A survivor of cancer with an MI has a threefold increased risk of dying compared with a noncancer person with an

MI.7 This is because the proximal coronary arteries, ing the left main and left anterior descending arteries, are directly in the fi eld of radiation

includ-Heart disease risk prediction models are often used in practice to estimate the 10-year risk of a serious cardiac event and then intervene with high-risk individuals by target-ing risk factors.13,14 Unfortunately, traditional risk prediction models for cardiovascular disease fail to account for cancer treatment–related risk factors Take, for example, a 52-year-old female with a history of Hodgkin lymphoma diagnosed

at the age of 22 years and treated with mediastinal radiation and chemotherapy, including cyclophosphamide, vincristine, procarbazine, and prednisone She is asymptomatic, does not smoke, has a total cholesterol of 210 mg per dL and a high-density lipoprotein (HDL) of 44 mg per dL, and a systolic blood pressure of 138 mm Hg Using the cardiovascular risk calculator on the National Heart, Lung, and Blood Institute15

website based on the Framingham Study, her risk is ⬍1% for having an MI or coronary death in the next 10 years However,

Cardiac and Pulmonary Sequelae of Cancer

and Its Treatment

Cardiac and pulmonary disease are the most common

non-cancer causes of serious morbidity and premature mortality

among long-term survivors of cancer.1–8 Thus, preventive

interventions and identifi cation and management of

early-stage disease are essential for the health and well-being

of many survivors of cancer.9–11 The primary care clinician

is integral in this process, particularly for cardiac sequelae,

because most outcomes will not be clinically evident until 10

or 20 years after the cancer therapy

CARDIAC SEQUELAE

Depending on treatment exposures, there is an excess risk of

ischemic coronary artery disease (CAD), heart failure (HF),

valvular heart disease, arrhythmias, and pericardial disease

(Table 39-1) As illustrated in Figure 39-1, CAD or HF can

result from direct injury to the heart muscle and coronary

arter-ies, respectively Comorbiditarter-ies, unhealthy lifestyle behaviors,

and genetic factors interact with treatment exposures and further

Trang 7

To date, studies of the use of stress exercise testing, cardiography, and radionucleotide imaging to screen for obstructive CAD in asymptomatic survivors have been incon-clusive.8 Stress echocardiography appears to be more sensi-tive and specifi c than other methods.25 However, this area of

echo-Lifestyle: tobacco, alcohol,

diet, physical activity

Therapy: mediastinal/neck radiation, anthracyclines,

alkylating agents, stem cell transplantation

FIGURE 39-1. Factors associated with cardiac sequelae in survivors of cancer.

TABLE 39-1 Cancer Therapies Associated with Cardiac Sequelae

Antitumor Class/Drug Most Frequent Toxicity Comments

LV dysfunction/HF Toxicity can be acute (within 24 hr), chronic (within 1 y) or late onset (after 1 y).

Monoclonal antibodies/small molecule inhibitors

Trastuzumab LV dysfunction/HF Increased incidence when combined with anthracyclines Toxicity is not dose dependent

and usually reversible.

Hypertension

Increased toxicity in age ⬎65 y and preexisting CVD.

Sunitinib Hypertension, HF Tyrosine kinase inhibitor that targets the vascular endothelial growth factor pathway; potential

for LV dysfunction recovery with interruption of drug and initiation of cardiac treatment Platinum agents

Fluorouracil Myocardial ischemia/MI

Atrial or ventricular arrhythmia

Possibly secondary to vasospasm; risk increased with co-existing CAD and concomitant cisplatin therapy

Capecitabine Same as mentioned previously

Radiotherapy Myocardial fi brosis with restrictive heart

disease, valvular disease, accelerated atherosclerosis, pericardial disease

Cardiac effects worsen over time with long latency between exposure and onset of symptoms

LV, left ventricular; HF, heart failure; MI, myocardial infarction; CVA, cerebrovascular accident; CVD, cardiovascular disease; CAD, coronary artery disease.

because of her mediastinal radiation, we know that her

10-year risk of MI or coronary death has been substantially

underestimated—based on available evidence, her risk is 10%

to 15%.16 Despite an apparently low-risk profi le based on a

traditional risk calculator, this patient’s cancer treatment

his-tory necessitates aggressive risk-reducing measures to prevent

a serious coronary event This vignette illustrates the lack of

appropriate tools available to clinicians when managing

long-term survivors of cancer Current studies are in progress to

develop risk prediction models for survivors of cancer

Ischemic CAD can result from indirect pathways For

example, therapy for childhood acute lymphoblastic leukemia

Trang 8

interval from therapy, and can occur even with low tive doses.28–35 Although the incidence of overt HF is low with conventional regimens, subclinical echocardiographic abnormalities of LV structure and function has been reported

cumula-in more than half of patients cumula-in the fi rst few years after cycline exposure and the abnormalities worsened over time

anthra-Importantly, HF can develop a decade or two after completion

of the anthracycline therapy Risk factors for induced HF include young age at therapy, cumulative doxo-rubicin dose, rate of administration, concurrent mediastinal

anthracycline-or chest radiation, female gender, preexisting heart disease, and hypertension Recent studies have identifi ed modify-ing genetic factors associated with anthracycline-related cardiomyopathy.36–38

The primary care clinician is an important member of the team for patients who may be treated with anthracycline che-motherapy as well as those who have completed their therapy

Before a patient starts on potentially LV cardiotoxic therapy, risk stratifi cation should be formulated based on treatment-related factors (type of drug, cumulative dose, combination

of potentially cardiotoxic treatment) and patient-specifi c risk factors (age, coexisting cardiovascular conditions, and prior history of cardiotoxic treatment) In high-risk patients, there should be a discussion between the oncologist, the primary care clinician, and a cardiologist assessing the oncologic benefi t of treatment and possible adverse cardiac risk, with consideration of cardioprotective measures or alteration of the treatment Optimization of the cardiovascular status (e.g., management of hypertension) prior to initiation of chemo-therapy is recommended with close cardiac monitoring during treatment so that an intervention can be initiated as soon as signs of cardiotoxicity are detected The American College of Cardiology (ACC)/American Heart Association (AHA) rec-ommend echocardiographic monitoring in patients who are at risk for HF (class I indication).39

For children, adolescents, and young adults who have completed anthracycline-based chemotherapy, the Children’s Oncology Group has developed evidence-informed recom-mendations for screening.26 The frequency of monitoring is based on cumulative anthracycline dose, age at exposure, and whether or not the patient was treated with chest radiation

Guidelines for posttherapy cardiac screening and follow-up

in asymptomatic survivors of adult cancer have not been established.8

The most common method for monitoring LV function during or after cancer therapy is measurement of LV ejec-tion fraction (LVEF) either by echocardiography or mul-tigated acquisition (MUGA) scan Other newer methods include cardiac magnetic resonance imaging (MRI) and 3-D echocardiography (Table 39-2) Because a broad range LVEF can be seen in healthy individuals, changes in LVEF indicative of cardiac damage can be identifi ed only when comparison between serial studies and pretreatment study are made Cardiotoxicity in recent major clinical trials has been defi ned as reduction of LVEF ⬎5% to ⬍55% with symptoms of HF or an asymptomatic reduction of LVEF of

⬎10% to ⬍55%

The natural history of anthracycline-induced LV function and its response to modern HF therapy has not been well established Mortality rates up to 50% within 2 years of diagnosis have been reported in the past, which is worse than many other forms of cardiomyopathy.40 Although ACC/AHA has published evidence-based treatment guidelines

dys-research is limited because of the relatively small number of

survivors available for study Because of the substantially

heightened risk of CAD and elevated risk of death from an MI

among pediatric and young adult survivors of cancer treated

with high-dose mediastinal radiation (ⱖ40 Gy), the Children’s

Oncology Group recommends consideration of cardiology

consultation 5 to 10 years after radiation.26

Regardless, studies consistently emphasize the importance

of modifi able traditional cardiovascular risk factors.1,2,7,8

Smoking and comorbid hypertension, dyslipidemia, and

dia-betes mellitus substantially increase the risk of ischemic CAD

in individuals treated with mediastinal radiation Thus, the

primary care clinician’s role in the care of survivors of

can-cer is critically important As with other high-risk populations

(i.e., patients with type 2 diabetes), it is essential that the

clini-cian screen for and manage hypertension, lipid disorders, and

diabetes and implement strategies for smoking cessation or

increasing level of physical activity as necessary

Left Ventricular Dysfunction and Heart Failure

Anthracycline chemotherapy (e.g., doxorubicin,

daunorubi-cin, epirubicin) is an important component in the treatment

of several types of cancer including breast, lung, endometrial,

and ovarian cancer; lymphoma; leukemia; and sarcoma In a

seminal study, von Hoff et al.27 reported that

anthracycline-induced cardiac injury is characterized by dose-dependent and

progressive left ventricular (LV) dysfunction, which can lead

to HF, developing within 1 year of treatment in 3% of patients

treated with a cumulative dose of 400 mg per m2 of

doxoru-bicin, 7% at 550 mg per m2, and 18% at 700 mg per m2

Sub-sequent studies have established that anthracycline-induced

LV dysfunction is common, risk increases with increasing

FIGURE 39-2. A 39-year-old man who was treated for Hodgkin lymphoma

25 years ago with 45 Gy mantle fi eld radiation The curved reconstruction of

coro-nary computed tomography (CT) angiogram shows two areas of severe

steno-sis (straight arrows) in left anterior descending coronary artery (LAD) and multiple

plaques (arrowhead) More distal LAD has relatively wide diameter and might

represent normal vessel or region of ectasia (curved arrow) (From Rademaker J,

Schoder H, Ariaratnam NS, et al Coronary artery disease after radiation therapy for

Hodgkin lymphoma: coronary CT angiography fi ndings and calcium scores in nine

asymptomatic patients AJR Am J Roentgenol 2008;191:32–37, with permission.)

Trang 9

hematopoi-Dose-related bleomycin-induced pneumonitis has long been recognized With contemporary therapy for germ cell tumors in men, this outcome is very uncommon because of limits in the total dose of bleomycin.47–49 Other chemother-apeutic agents that are associated with pulmonary disease include busulfan, carmustine, and lomustine Combination of pulmonary toxic chemotherapy with chest radiation increases the risk of pulmonary disease Survivors of Hodgkin lym-phoma treated with chest radiation in combination with bleo-mycin frequently have pulmonary problems; fortunately, these are generally mild to moderate in severity.50,51

The natural history of treatment-related pulmonary ease, particularly 10 years or more after therapy, is not well described Thus, the optimum frequency and duration of monitoring pulmonary function is not known.8 As previ-ously mentioned, it is imperative that survivors of cancer treated with potentially pulmonary toxic therapy avoid or stop smoking

dis-for HF in general,41,42 the effectiveness of therapy in

anthra-cycline-related HF has not been well established Given the

well-established fi nal common pathway of remodeling and

compensation in systolic HF, treatment for

chemotherapy-related LV dysfunction based on current HF management

guideline is recommended

Valvular Heart Disease and Arrhythmias

Mediastinal (chest radiation) occasionally causes valvular

heart disease, predominantly involving the aortic and mitral

valves.43 About 6% of survivors treated with moderate- to

high-dose mediastinal radiation develop clinically signifi cant

valvular disease and have an eightfold higher likelihood of

valve surgery.44 Evaluation for and monitoring of valvular

heart disease in survivors treated with mediastinal radiation

can be accomplished with periodic echocardiography.8,26

Importantly, survivors of cancer with valvular heart disease

following mediastinal radiation have a higher incidence of

perioperative morbidity.45

Life-threatening arrhythmias, including complete heart

block, are rare outcomes following cancer therapy and are

generally attributable to mediastinal radiation Prolongation

of QTc infrequently occurs following anthracycline therapy.46

As in the general population, the patient should be counseled

about the use of medications that may prolong the QT interval

such as antifungal agents and metronidazole

TABLE 39-2 Assesment of Cardiac Function

MUGA scan Reproducible LVEF measurement with low interobserver and

intraobserver variability

Radiation exposure; limited information on cardiac structure and diastolic function

2-D echocardiography Low cost, easy to perform and widely available; no radiation

exposure; comprehensive evaluation of cardiac structure and function

High intraobserver and interobserver variability of LVEF calculation because of dependency on image quality, geometric assumption, and operator expertise May fail to detect subtle changes in LVEF

3-D echocardiography Same as 2-D echo; highly reliable LVEF calculation Limited data on its use in monitoring cardiotoxicity; not yet

incorporated into routine clinical practice MRI Accurate and reliable assessment of LVEF; gold standard in the

measurement of LV volume, structure, and systolic function; can detect myocardial fi brosis and scarring when combined with late gadolinium contrast enhancement

High cost and not widely available

MUGA, multigated acquisition scan; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; LV, left ventricular.

References

1 Aleman BM, van den Belt-Dusebout AW, De Bruin ML, et al Late

car-diotoxicity after treatment for Hodgkin lymphoma Blood 2007;109:

1878–1886.

2 Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al Long-term

cause-specifi c mortality of patients treated for Hodgkin’s disease J Clin

Oncol 2003;21:3431–3439.

3 Chapman JA, Meng D, Shepherd L, et al Competing causes of death from a randomized trial of extended adjuvant endocrine therapy for

breast cancer J Natl Cancer Inst 2008;100:252–260.

4 Hooning MJ, Aleman BM, van Rosmalen AJ, et al Cause-specifi c tality in long-term survivors of breast cancer: a 25-year follow-up study

mor-Int J Radiat Oncol Biol Phys 2006;64:1081–1091.

Trang 10

27 Von Hoff DD, Layard MW, Basa P, et al Risk factors for

doxorubicin-induced congestive heart failure Ann Intern Med 1979;91:710–717.

28 Du XL, Xia R, Burau K, et al Cardiac risk associated with the receipt

of anthracycline and trastuzumab in a large nationwide cohort of older

women with breast cancer Med Oncol 2010:1998–2005.

29 Du XL, Xia R, Liu C, et al Cardiac toxicity associated with

anthracycline-containing chemotherapy in older women with breast cancer Cancer

2009;115:5296–5308.

30 Lipshultz SE, Colan SD, Gelber RD, et al Late cardiac effects of

doxo-rubicin therapy for acute lymphoblastic leukemia in childhood N Engl J Med 1991;324:808–815.

31 Lipshultz SE, Lipsitz SR, Sallan SE, et al Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lympho-

blastic leukemia J Clin Oncol 2005;23:2629–2636.

32 Pinder MC, Duan Z, Goodwin JS, et al Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast

cancer J Clin Oncol 2007;25:3808–3815.

33 Sawaya H, Sebag IA, Plana JC, et al Early detection and prediction of

cardiotoxicity in chemotherapy-treated patients Am J Cardiol 2011;107:

1375–1380.

34 Swain SM, Whaley FS, Ewer MS Congestive heart failure in patients

treated with doxorubicin: a retrospective analysis of three trials Cancer

2003;97:2869–2879.

35 van Dalen EC, van der Pal HJ, Kok WE, et al Clinical heart failure in

a cohort of children treated with anthracyclines: a long-term follow-up

study Eur J Cancer 2006;42:3191–3198.

36 Blanco JG, Sun CL, Landier W, et al Anthracycline-related myopathy after childhood cancer: role of polymorphisms in carbonyl

reductase genes—A report from the Children’s Oncology Group J Clin Oncol 2011.

37 Visscher H, Ross CJ, Rassekh SR, et al Pharmacogenomic prediction of

anthracycline-induced cardiotoxicity in children J Clin Oncol 2011.

38 Wojnowski L, Kulle B, Schirmer M, et al NAD(P)H oxidase and tidrug resistance protein genetic polymorphisms are associated with

mul-doxorubicin-induced cardiotoxicity Circulation 2005;112:3754–3762.

39 Cheitlin MD, Armstrong WF, Aurigemma GP, et al Guideline update for the clinical application of echocardiography—summary article: a report of the American College of Cardiology/American Heart Associa- tion Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiog-

raphy) J Am Coll Cardiol 2003;42:954–970.

40 Felker GM, Thompson RE, Hare JM, et al Underlying causes and term survival in patients with initially unexplained cardiomyopathy

long-N Engl J Med 2000;342:1077–1084.

41 Hunt SA, Abraham WT, Chin MH, et al 2009 Focused update porated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults A report of the American College

incor-of Cardiology Foundation/American Heart Association Task Force

on practice guidelines developed in collaboration with the

Interna-tional Society for Heart and Lung Transplantation J Am Coll Cardiol

2009;53:e1–e90.

42 Hunt SA, Baker DW, Chin MH, et al ACC/AHA guidelines for the uation and management of chronic heart failure in the adult: executive summary A report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines (Committee to revise the 1995 guidelines for the evaluation and management of heart

eval-failure) J Am Coll Cardiol 2001;38:2101–2113.

43 Adams MJ, Lipsitz SR, Colan SD, et al Cardiovascular status in term survivors of Hodgkin’s disease treated with chest radiotherapy

long-J Clin Oncol 2004;22:3139–3148.

5 Mertens AC, Liu Q, Neglia JP, et al Cause-specifi c late mortality among

5-year survivors of childhood cancer: the Childhood Cancer Survivor

Study J Natl Cancer Inst 2008;100:1368–1379.

6 Ng AK, Bernardo MP, Weller E, et al Long-term survival and competing

causes of death in patients with early-stage Hodgkin’s disease treated at

age 50 or younger J Clin Oncol 2002;20:2101–2108.

7 Swerdlow AJ, Higgins CD, Smith P, et al Myocardial infarction

mortal-ity risk after treatment for Hodgkin disease: a collaborative British cohort

study J Natl Cancer Inst 2007;99:206–214.

8 Carver JR, Shapiro CL, Ng A, et al American Society of Clinical

Oncol-ogy clinical evidence review on the ongoing care of adult cancer

sur-vivors: cardiac and pulmonary late effects J Clin Oncol 2007;25:

3991–4008.

9 Hewitt M, Greenfi eld S, Stovall E, eds From Cancer Patient to Cancer

Survivor: Lost in Transition Washington, DC: Committee on Cancer

Survivorship: Improving Care and Quality of Life, National Cancer

Policy Board, Institute of Medicine, and National Research Council,

National Academies Press; 2005.

10 Oeffi nger KC, Hudson MM, Landier W Survivorship: childhood cancer

survivors Prim Care 2009;36:743–780.

11 Oeffi nger KC, McCabe MS Models for delivering survivorship care

J Clin Oncol 2006;24:5117–5124.

12 Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al Ischemic heart

disease after mantlefi eld irradiation for Hodgkin’s disease in long-term

follow-up Radiother Oncol 1999;51:35–42.

13 Mosca L, Benjamin EJ, Berra K, et al Effectiveness-based

guide-lines for the prevention of cardiovascular disease in women—2011

update: a guideline from the American Heart Association Circulation

2011;123:1243–1262.

14 U.S Preventive Services Task Force Aspirin for the prevention of

car-diovascular disease: U.S Preventive Services Task Force

recommenda-tion statement Ann Intern Med 2009;150:396–404.

15 National Heart Lung and Blood Institute http://www.nhlbi.nih.gov/

Accessed April 10, 2012.

16 Aleman BMP, van den Belt-Dusebout AW, De Bruin ML, et al

Late cardiotoxicity after treatment for Hodgkin lymphoma Blood

2007;109:1878–1886.

17 Oeffi nger KC Are survivors of acute lymphoblastic leukemia (ALL)

at increased risk of cardiovascular disease? Pediatr Blood Cancer

2008;50:462–467; discussion 468.

18 Feldman DR, Bosl GJ, Sheinfeld J, et al Medical treatment of advanced

testicular cancer JAMA 2008;299:672–684.

19 Haugnes HS, Aass N, Fossa SD, et al Components of the metabolic

syndrome in long-term survivors of testicular cancer Ann Oncol

2007;18:241–248.

20 Haugnes HS, Aass N, Fossa SD, et al Predicted cardiovascular

mortal-ity and reported cardiovascular morbidmortal-ity in testicular cancer survivors

J Cancer Surviv 2008;2:128–137.

21 Haugnes HS, Wethal T, Aass N, et al Cardiovascular risk factors and

morbidity in long-term survivors of testicular cancer: a 20-year follow-up

study J Clin Oncol 2010;28:4649–4657.

22 van den Belt-Dusebout AW, Nuver J, de Wit R, et al Long-term risk

of cardiovascular disease in 5-year survivors of testicular cancer J Clin

Oncol 2006;24:467–475.

23 Feldman DR, Schaffer WL, Steingart RM Late cardiovascular toxicity

following chemotherapy for germ cell tumors J Natl Compr Canc Netw

2012;10:537–544.

24 Vaughn DJ, Palmer SC, Carver JR, et al Cardiovascular risk in long-term

survivors of testicular cancer Cancer 2008;112:1949–1953.

25 Heidenreich PA, Schnittger I, Strauss HW, et al Screening for coronary

artery disease after mediastinal irradiation for Hodgkin’s disease J Clin

Oncol 2007;25:43–49.

Trang 11

Ch a p t e r 3 9 / C a rd i a c a n d P u l m o n a r y S e q u e l a e o f C a n c e r a n d I t s Tre a t m e n t 247

48 Loehrer PJ Sr, Johnson D, Elson P, et al Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Coopera-

tive Oncology Group trial J Clin Oncol 1995;13:470–476.

49 Nichols CR, Catalano PJ, Crawford ED, et al Randomized parison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group,

com-and Cancer com-and Leukemia Group B Study J Clin Oncol 1998;16:

51 Lund MB, Kongerud J, Nome O, et al Lung function impairment in

long-term survivors of Hodgkin’s disease Ann Oncol 1995;6:495–501.

44 Hull MC, Morris CG, Pepine CJ, et al Valvular dysfunction and

carotid, subclavian, and coronary artery disease in survivors of hodgkin

lymphoma treated with radiation therapy JAMA 2003;290:2831–2837.

45 Chang AS, Smedira NG, Chang CL, et al Cardiac surgery after

medias-tinal radiation: extent of exposure infl uences outcome J Thorac

Cardio-vasc Surg 2007;133:404–413.

46 Gupta M, Thaler HT, Friedman D, et al Presence of prolonged

disper-sion of qt intervals in late survivors of childhood anthracycline therapy

Pediatr Hematol Oncol 2002;19:533–542.

47 de Wit R, Roberts JT, Wilkinson PM, et al Equivalence of three or four

cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a

3- or 5-day schedule in good-prognosis germ cell cancer: a

random-ized study of the European Organization for Research and Treatment of

Cancer Genitourinary Tract Cancer Cooperative Group and the Medical

Research Council J Clin Oncol 2001;19:1629–1640.

Trang 12

Bone Health 40

CHAPTER

KEY POINTS

• Cancer and cancer therapy can cause a failure to reach

peak bone mass and/or accelerate bone loss via several

mechanisms.

• Bone density evaluation should be considered for children

and adolescents treated with cancer therapies that prevent

peak bone mass and for all survivors of cancer treated

with therapies associated with accelerated bone loss.

• For individuals younger than the age of 50 years, z scores

are used to assess bone mineral density.

• Recommendations for initiation of antiresorptive therapy

for survivors of adult cancer are similar to persons without

a history of cancer.

• Referral to an endocrinologist should be considered for

survivors of childhood cancer with very low bone mass

( z score 2.5).

Susan Hong, MD, MPH • Marina Rozenberg, MD • Kevin C Oeffinger, MD

adolescents Thus, bone remodeling involves a complex network of cells and signals, which, if disrupted, can nega-tively impact bone health

Childhood cancer and its treatment coincide with a vital period of bone growth, interfering with the acquisition of maximal bone density and leading to increased bone loss via several mechanisms (Table 40-1) The Children’s Oncol-ogy Group (COG) provides updated evidence-based guide-lines for screening for early- and late-occurring sequelae following therapy for pediatric cancer, including bone-related morbidity.5 Table 40-2 provides a synopsis of these recommendations

Survivors of adult cancer are at increased risk for erated bone loss through several mechanisms (Table 40-3)

accel-The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) rec-ommend monitoring of bone mineral density (BMD) in men and women who have undergone cancer therapy that nega-tively impacts bone health Dual-energy X-ray absorptiometry (DEXA) scans are used to measure BMD; however, there are limitations with this approach in children

Lifestyle modifi cation is recommended for everyone regardless of BMD (Table 40-4) The World Health Orga-nization (WHO) fracture risk algorithm (FRAX) calculates the 10-year probability of hip and major osteoporotic frac-ture risk The NCCN Task Force on Bone Health in Cancer Care recommends using the WHO FRAX algorithm to assess baseline fracture risk for all patients with cancer at risk for bone loss.6 Pharmacotherapy is generally indicated for patients with osteoporosis or a history of fragility frac-tures (Tables 40-2 and 40-5) As in persons without a his-tory of cancer, bisphosphonates are usually fi rst line to treat bone loss when clinically indicated Denosumab is a newly U.S Food and Drug Administration (FDA)–approved monoclonal antibody that interferes with RANK ligand binding and is also approved to treat bone loss.7 Teripara-tide is a recombinant human parathyroid hormone, which can be used to build bone in individuals with severe osteo-porosis It is seldom used in survivors of cancer because

of concerns about the risk of subsequent osteosarcoma.8

Treatment for survivors of childhood cancer with phonates may be considered, but evaluation with an endo-crinologist is recommended

bisphos-Osteoporosis is a systemic disorder of the skeletal system

characterized by low bone mass and deterioration in the

bone tissue microarchitecture leading to an increased risk

of bone fractures.1 Cancer and cancer treatments often

negatively impact bone health, resulting in higher rates of

osteoporosis and subsequent fractures among survivors of

cancer

Bone remodeling continues throughout life Peak bone

mass is achieved by 18 to 20 years of age After the age

of 35 years, bone resorption exceeds formation Adequate

bone mineralization is crucial to bone health and is

depen-dent on vitamin D, calcium, magnesium, phosphorus, and

other trace elements.2 Important factors in bone

remod-eling include the receptor activator for nuclear factor B

(RANK) pathway, which stimulates bone resorption via

osteoclast activation, and hormones such as estrogen and

growth hormone (GH) Estrogen inhibits osteoclast-driven

resorption and promotes bone formation by

stimulat-ing osteoblast activity.3 In males, estrogen is formed by

the aromatization of testosterone and is thus dependent

on adequate testosterone levels.4 Adequate levels of GH

are essential for bone density acquisition in children and

Trang 13

Ch a p t e r 4 0 / B o n e H e a l t h 249

TABLE 40-1 Childhood Cancer Therapy Associated with Reduced Bone Mineral Density

Therapy Used for Mechanism of Bone Loss

Corticosteroids Supportive therapy, chemotherapy

Directly toxic to osteoblasts Increases osteoclast formation Total dose 40 g/m 2 is associated with highest risk for osteopenia 9

Confer risk of premature menopause/ovarian failure/Leydig cell dysfunction Concurrent radiation potentiates gonadal toxicity 10

Radiation therapy

Cranial radiation Brain tumors, ALL Doses 18 Gy to the HPA associated with GH defi ciency.

Doses 40 Gy to the HPA may cause gonadotropin defi ciency 10

Radiation to abdomen & pelvis

Ovarian failure/estrogen defi ciency and Leydig cell dysfunction/androgen defi ciency 10

Surgical castration

Orchiectomy

Testicular cancer Rapid loss of androgens result in loss of estrogen

ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; HSCT, hematopoietic stem cell transplant; GH, growth hormone; Gy, gray; HPA, hypothalamic-pituitary-adrenal axis;

TBI, total body irradiation.

TABLE 40-2 Evaluation and Management of Bone Health in Childhood Cancer Survivors

Recommendations

For patients who received therapies that have negative impact on

bone health (see Table 40-1)

For individuals 50 y, use z scores, which compares measured BMD to BMD of age-, gender-,

and ethnicity-matched controls.

Based on z-score results

Normal (z score 1.0) If not at risk for ongoing bone loss, consider stopping until menopause Consider restarting

screening if clinically indicated.

Osteoporosis (z 2.5 or fragility fracture, i.e., a fracture that

results from a fall from a standing height or less)

Refer to endocrinology for consideration of possible contributing factors for severe bone loss

Consider treatments when appropriate Repeat BMD as clinically indicated (usually every 2 y)

BMD, bone mineral density.

Trang 14

TABLE 40-3 Adult Cancer Therapy Associated with Reduced Bone Mineral Density

Therapy Used in Mechanism of Bone Loss Degree and Site of Bone Loss

Aromatase inhibitors Hormone sensitive breast

cancer

Inhibit peripheral conversion of androgen to estrogen (reduces estrone sulfate, estradiol, estrogen)

↓ 4.1% in LS after 2 y 11

sensitive breast cancer

Potentially interferes with estrogen action on bone when used in premenopausal women but not in postmenopausal women

↓ 1.44%/y in LS (unclear if increased fracture risk) 12

Decrease LH and FSH receptors Decrease testosterone Decrease estrogen (via decreased testosterone conversion to estradiol)

↓ 4%–10% in LS the fi rst year, then ↓ 4%–5% per year with sustained use 13

Corticosteroids Supportive therapy,

Impair calcium absorption

Impact greater on cancellous bone than cortical bone.

Fractures typically occur at higher BMD than with natural menopause.

Chemotherapy

Cisplatin

Carboplatin

Ovarian cancer Breast cancer Germ cell tumors

Magnesium wasting leads to increased osteoclast activity through activation of the RANK pathway 8

No data on degree of bone loss

Premenopausal breast cancer Premature menopause

Depletion of estrogen and androgens

Greater loss of BMD than with natural menopause

Surgical castration

Orchiectomy

Oophorectomy

Prostate cancer Testicular cancer Breast cancer Ovarian cancer

Rapid depletion of sex hormones Rapid loss of BMD; increased fracture risk

↓, decrease; LS, lumbar spine; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; BMD, bone mineral density; RR, relative risk; RANK, receptor

activa-tor of nuclear facactiva-tor ␬B

For All Cancer Survivors Recommendations

Calcium from food is best supplement if/when needed (calcium citrate is

better absorbed than carbonate)

1,200 mg/d in divided doses

T score less than 1.0, check 25-OH vitamin D levels and target to levels 30 ng/mL 6

a For all cancer survivors regardless of age, calcium and vitamin D recommendations are the equivalent National Osteoporosis Foundation guidelines for individuals aged 50 years and older.

NCCN, National Comprehensive Cancer Network; GH, growth hormone.

TABLE 40-4 Recommendations by NCCN for All Cancer Survivors Regardless of Menopausal Status a

Trang 15

Ch a p t e r 4 0 / B o n e H e a l t h 251

TABLE 40-5 Evaluation and Management of Bone Health in Adults

Evaluation and Management

healthy adults.

bone health (see Table 40-3).

Recommendations based on t-score results

Normal (t 1) If not at increased risk for ongoing bone loss, consider stopping BMD testing until menopause 8

Osteopenia (1.0 t 2.5), and if all the following apply:

1) No history of fragility fracture

2) FRAX 10-y hip fracture risk 3%

3) FRAX 10-y osteoporotic fracture risk 20%

Repeat BMD as clinically indicated, usually every 2 y 4,6

Check 25-OH vitamin D level and treat to levels 30 ng/mL 6

NCCN guidelines—start antiresorptive therapy for t score 2.0 6

Osteoporosis (t 2.5) or if any of the following apply:

1) History of fragility fracture

2) FRAX 10-y hip fracture risk 3%

3) FRAX 10-y osteoporotic fracture risk 20%

Antiresorptive therapy Continue BMD testing (in some individuals, may be appropriate to retest after a year).

Check 25-OH vitamin D level and target values 30 ng/mL 6

BMD, bone mineral density; ASCO, American Society of Clinical Oncology; NCCN, National Comprehensive Cancer Network.

From Children’s Oncology Group Long-term Follow-up Guidelines for Survivors of Childhood, Adolescents, and Young Adult Cancers Version 3.0 http://www.survivorshipguidelines.org Accessed December 16, 2012;

NCCN Task Force Report: bone health in cancer care J Natl Compr Canc Netw 2009; 7(suppl 3):S1–S32; quiz S33–S35.

References

1 Consensus development conference: diagnosis, prophylaxis, and

treat-ment of osteoporosis Am J Med 1993;94(6):646–650.

2 Santen RJ Clinical review: effect of endocrine therapies on bone in

breast cancer patients J Clin Endocrinol Metab 2011;96(2):308–319.

3 Lee BL, Higgins MJ, Goss PE Denosumab and the current status of

bone-modifying drugs in breast cancer Acta Oncol 2012;51(2):157–167.

4 Sandhu SK, Hampson G The pathogenesis, diagnosis, investigation and

management of osteoporosis J Clin Pathol 2011;64(12):1042–1050.

5 Children’s Oncology Group Long-Term Follow-up Guidelines for

Sur-vivors of Childhood, Adolescent, and Young Adult Cancers Version 3.0

http://www.survivorshipguidelines.org Accessed December 16, 2012.

6 NCCN Task Force Report: bone health in Cancer Care J Natl Compr

Canc Netw 2009;7(suppl 3):S1–S32; quiz S33–S55.

7 Brown JE, Coleman RE Denosumab in patients with cancer—a surgical

strike against the osteoclast Nat Rev Clin Oncol 2011;9(2):110–118.

8 Wickham R Osteoporosis related to disease or therapy in patients with

cancer Clin J Oncol Nurs 2011;15(6):E90–E104.

9 Wasilewski-Masker K, Kaste SC, Hudson MM, et al Bone mineral

den-sity defi cits in survivors of childhood cancer: long-term follow-up

guide-lines and review of the literature Pediatrics 2008;121(3):e705–e713.

10 Landier W, eds Establishing and Enhancing Services for Childhood Cancer Survivors Long-term Follow-up Program Resource Guide

Arcadia, CA: CureSearch Children’s Oncology Group; 2007.

11 Hadji P Aromatase inhibitor-associated bone loss in breast cancer

patients is distinct from postmenopausal osteoporosis Crit Rev Oncol Hematol 2009;69(1):73–82.

12 Powles TJ, Hickish T, Kanis JA, et al Effect of tamoxifen on bone eral density measured by dual-energy x-ray absorptiometry in healthy

min-premenopausal and postmenopausal women J Clin Oncol 1996;14(1):

15 Shahinian VB, Kuo YF, Freeman JL, et al Risk of fracture after

androgen deprivation for prostate cancer N Engl J Med 2005;352(2):

154–164.

Trang 16

Fertility 41

CHAPTER

KEY POINTS

• Many cancer treatments affect fertility.

• Many cancer survivors want to be parents after cancer

treatment.

• Most postpubertal patients can preserve fertility before

treatment begins if they are informed of the risks and

options early during treatment planning.

Joanne Frankel Kelvin, RN, MSN • Glenn L Schattman, MD

the cessation of menses.16 Additional effects of cancer ment on fertility are described in Table 41-2

treat-BEFORE BEGINNING TREATMENT

Postpubertal males can cryopreserve sperm prior to ment and should be encouraged to bank at least three semen samples Sperm banking is noninvasive, does not delay treat-ment, and is relatively inexpensive.2 Later use of this limited quantity of cryopreserved sperm is most effi cient if used in conjunction with in vitro fertilization.17 Other FP options are available for postpubertal males who are unable to masturbate

treat-or who have impaired fertility beftreat-ore treatment begins and ftreat-or prepubertal males who have not yet initiated spermatogen-esis.2,18 These are summarized in Table 41-3

Women can cryopreserve oocytes or embryos, but this is expensive and takes 2 to 3 weeks It requires daily hormone injections, monitoring with regular blood tests and ultrasound examinations, and a transvaginal needle aspiration under sedation to retrieve oocytes Early referrals to reproductive specialists can ensure patients have time to do this without signifi cantly delaying treatment Other FP options are avail-able for postpubertal and prepubertal females5,19–21 and are summarized in Table 41-3

FP decisions must be made before treatment begins, because once the patient has received gonadal radiation or systemic chemotherapy, collection of gametes is discouraged because of risk of damage and poor outcomes.22 With knowl-edge of their patients’ desires for children, health concerns, values and beliefs, and social situation, PCCs can effectively counsel patients while they make decisions whether or not to pursue FP Ensuring patients are informed and participate in the decision making minimizes the likelihood of regret in the future regardless of their reproductive outcomes.23

AFTER TREATMENT IS COMPLETED

Evaluating gonadal function after treatment helps individuals understand their fertility potential In males, a semen analysis will evaluate for the presence of sperm and measure density, motility, and morphology Some men will be infertile imme-diately after treatment but will recover spermatogenesis This occurs most often within 3 years but has been seen to occur even many years after treatment is completed.13

Many women will cease menstruation during treatment because of the effects of treatment on developing follicles but

About 164,000 men and women younger than 45 years of age

are diagnosed with cancer each year in the United States.1

Treatments including surgery, chemotherapy, and radiation

have resulted in improved survival; however, they can

nega-tively affect future fertility.2 Unfortunately, many patients are

not informed of these risks before beginning treatment3–5 and

thus cannot take advantage of advances in reproductive

tech-nology that may enable them to preserve fertility potential

before treatment Primary care clinicians (PCCs) can play a

signifi cant role as advocates for their patients—ensuring they

get the information and referrals they need to understand their

risks and decide whether or not to pursue fertility preservation

(FP) before treatment begins and to learn of options for

build-ing a family after treatment is completed

EFFECTS OF TREATMENT

The impact of chemotherapy or radiation on future

repro-ductive capability depends on several factors, including the

quantity and quality of gametes in the gonads prior to

treat-ment, the gonadotoxicity of the agents used, the dose of each

agent, and the number of potentially gonadotoxic agents

given Risks of selected chemotherapy agents are outlined

in Table 41-12,6–12; however, there are many new drugs and

regimens for which the risks are unknown It is impossible

to predict with certainty who will have permanent gonadal

failure Men continually produce new gametes after puberty

and may recover spermatogenesis after treatment.13 Women

are born with a fi nite supply of gametes and they continually

deplete with age.14,15 This loss is hastened by gonadotoxic

therapy, potentially resulting in premature ovarian failure The

diffi culty in predicting risk is compounded by the fact that

research on fertility risks in females often uses amenorrhea as

the outcome; however, fertility declines many years prior to

Trang 17

Ch a p t e r 4 1 / F e r t i l i t y 253

depending on their age and treatment may resume menses

within the fi rst year after treatment is completed However, as

discussed previously, resumption of menses does not guarantee

fertility Measures of ovarian reserve to evaluate fertility include

transvaginal ultrasound to count potential follicles in the

ova-ries, anti-müllerian hormone (AMH) levels, and, in

menstruat-ing females, day 3 follicle-stimulatmenstruat-ing hormone (FSH) levels.24

The oncologist should determine when it is safe for the patient

to try to start a family—to pass the time interval when he or she

is at the greatest risk of an early recurrence, to ensure damaged

TABLE 41-2 Potential Fertility Effects of

Cancer Treatment

Males

• Depletion of spermatogonial germ cells with oligospermia or azoospermia (C, RT)

• Leydig cell dysfunction with reduced testosterone production (C, RT, S)

• Injury to genitourinary ductal system with impaired transport of sperm during ejaculation (RT, S)

• Injury to genitourinary nerves and blood vessels with erectile or ejaculatory dysfunction (RT, S)

• Injury to pituitary gland with impaired hormonal regulation of spermatogenesis (RT, S)

• Loss of reproductive structures with inability to conceive or carry a pregnancy (S)

• Injury to pituitary gland with impaired hormonal regulation of menses (RT, S)

C, chemotherapy; RT, radiation therapy; S, surgery.

gametes have been eliminated, and to ensure the patient has recovered from treatment This time is generally 1 to 3 years

If semen parameters are normal or ovarian function is present, patients should fi rst try to conceive naturally If unsuccessful after 3 to 6 months, referral to a reproductive specialist for evaluation and treatment is warranted Patients may be able to use their own gametes to conceive; others will

be interested in pursuing alternative options for building a family These include use of donor sperm or eggs, gestational carriers (for women who have had a hysterectomy, received high-dose pelvic radiation, or are at risk for recurrence if they were to carry a pregnancy), or adoption A history of cancer does not preclude adoption, but patients generally have to be cancer free for at least 5 years These alternative options for building a family are summarized in Table 41-4

Young women who are not ready to start a family but are

at risk for premature ovarian failure can consider fertility preservation with oocyte or embryo cryopreservation after treatment once cleared by their oncologist

RESOURCES

The treating oncologist should have a network of sperm banks and reproductive specialists to whom they can refer patients interested in pursuing one of these options The process can be complicated, time consuming, costly, and stressful However, with the support of a multidisciplinary team and the ongoing advances in reproductive technology, the process can be extremely rewarding for your patients PCCs can encourage their patients to speak with their oncologists about their desires and concerns, provide resources for them to access informa-tion at their own pace, and guide them toward resources for

fi nancial assistance Table 41-5 lists resources you can share with your patients

Single Agents Risk of Infertility

Multiagent Regimens Risk of Infertility

Testicular cancer

Any regimen with cisplatin or carboplatin Intermediate

Breast cancer

CMF (cyclophosphamide, methotrexate, fl uorouracil) Intermediate high

AC (doxorubicin, cyclophosphamide) Low intermediate

Hodgkin lymphoma

ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) Low

VAPEC-B (vincristine, doxorubicin, prednisone, etoposide,

cyclophosphamide, and bleomycin)

Low

VACOP-B (vinblastine, doxorubicin, cyclophosphamide,

vincristine, prednisone, and bleomycin)

MACOP-B (methotrexate, doxorubicin, cyclophosphamide,

vincristine, prednisone, and bleomycin)

VEEP (vincristine, etoposide, epirubicin, and prednisolone)

Hematopoietic cell transplant

All conditioning regimens ( ↑ risk with total body irradiation) High

Risks of specifi c agents are dose related, and in females, are age related, with increased risk at

increased age.

↑, high/increase.

TABLE 41-1 Risk of Infertility from Chemotherapy

Trang 18

Males

Sperm cryopreservation

Sperm banking

For postpubertal males able to obtain a semen sample by masturbation

• Home collection kits are available if no local sperm bank: Live:On (Fertile Hope), OverNite Male (Reprotech)

Electroejaculation

For males unable to masturbate for physical, emotional, religious, or cultural reasons

• Collected by a reproductive urologist in the OR under anesthesia; ejaculation stimulated by an electrical current from a rectal probe placed over the prostate gland

Testicular sperm extraction/epididymal aspiration

For males with obstruction of the vas deferens or impaired spermatogenesis and who are azoospermic on semen analysis

• Collected by a reproductive urologist in the OR, under anesthesia, through testicular biopsy, microsurgical epididymal aspiration, or percutaneous aspiration

Testicular tissue cryopreservation

For prepubertal males

• Collected by a reproductive urologist in the OR under anesthesia, through testicular biopsy

• Investigational; no live human births from reimplantation of tissue to date.

Testicular shielding

For males getting pelvic radiation

• Use of external shields to protect the testes from the effects of radiation

Females

Embryo cryopreservation

For females with a partner or willing to use donor sperm

• Freezing of embryos obtained by ovarian stimulation, egg retrieval, and in vitro fertilization

Oocyte cryopreservation

For females with no partner and unwilling to use donor sperm or patients with ethical concerns about freezing embryos

• Freezing of unfertilized eggs obtained by ovarian stimulation and egg retrieval

Ovarian tissue cryopreservation

For prepubertal females or those who cannot delay treatment for ovarian stimulation

• Collected in the OR under anesthesia

• Investigational; only 18 live human births reported from reimplantation of tissue to date.

Ovarian transposition

For females getting pelvic radiation

• Surgical placement of ovaries out of the fi eld of radiation

Ovarian suppression

For females getting chemotherapy

• Use of GnRH agonists to suppress ovarian function

• Investigational; data on effectiveness is confl icting.

OR, operating room; GnRH, gonadotropin-releasing hormone.

TABLE 41-3 Options for Fertility Preservation Before Treatment

Trang 19

Ch a p t e r 4 1 / F e r t i l i t y 255

10 Meirow D, Biederman H, Anderson RA, et al Toxicity of

chemo-therapy and radiation on female reproduction Clin obstet Gynecol

2010;53(4):727–739 doi:10.1097/GRF.0b013e3181f96b54.

11 Stroud JS, Mutch D, Rader J, et al Effects of cancer treatment on ovarian

function Fertil Steril 2009;92(2):417–427.

12 Wo JY, Viswanathan AN Impact of radiotherapy on fertility, pregnancy,

and neonatal outcomes in female cancer patients Int J Radiat Oncol Biol Phys 2009;73(5):1304–1312.

13 Howell SJ, Shalet SM Spermatogenesis after cancer treatment: damage

and recovery J Natl Cancer Inst Monographs 2005;2005(34):12–17.

14 Oktem O, Oktay K The ovary: anatomy and function throughout human

life Ann N Y Acad Sci 2008;1127:1–9.

15 de Bruin JP, Dorland M, Spek ER, et al Age-related changes in the

ultrastructure of the resting follicle pool in human ovaries Biol Reprod

2004;70(2):419–424.

16 Letourneau JM, Ebbel EE, Katz PP, et al Acute ovarian failure underestimates age-specifi c reproductive impairment for young women

undergoing chemotherapy for cancer Cancer 2011.

17 Hourvitz A, Goldschlag DA, Davis OK, et al Intracytoplasmic sperm injection (ICSI) using cryopreserved sperm from men with

malignant neoplasm yields high pregnancy rates Fertil Steril 2008;

1 Surveillance Epidemiology and End Results Age-distribution of

inci-dence cases SEER Cancer Statistics Review 1975–2008 http://seer

.cancer.gov/csr/1975_2008/browse_csr.php?section=1&page=sect_01

_table.10.html Accessed November 7, 2011.

2 Lee SJ, Schover LR, Partridge AH, et al American society of clinical

oncology recommendations on fertility preservation in cancer patients

J Clin Oncol 2006;24(18):2917–2931.

3 Peate M, Meiser B, Hickey M, et al The fertility-related concerns, needs

and preferences of younger women with breast cancer: a systematic

review Breast Cancer Res Treat 2009;(116):215–223.

4 Tschudin S, Bitzer J Psychological aspects of fertility preservation in

men and women affected by cancer and other life-threatening diseases

Hum Reprod Update 2009;15(5):587–597.

5 Duffy C, Allen S Medical and psychosocial aspects of fertility after

cancer Cancer J 2009;15(1):27–33.

6 Magelssen H, Brydoy M, Fossa SD The effects of cancer and cancer

treatments on male reproductive function Nat Clin Pract Urol 2006;

3(6):312–322.

7 Meistrich ML Male gonadal toxicity Pediatr Blood Cancer 2009;

53(2):261–266.

8 Yamaguchi K, Fujisawa M Anticancer chemotherapeutic agents and

testicular dysfunction Reprod Med Biol 2011;10:81–87.

9 Maltaris T Seufert R, Fischl F, et al The effect of cancer treatment

on female fertility and strategies for preserving fertility Eur J Obstet

Gynecol Reprod Biol 2007;130(2):148–155.

TABLE 41-4 Alternative Options for Building a

Family After Treatment Is Completed

Males

Patient’s frozen sperm

• Sperm thawed and used for in vitro fertilization

Testicular sperm extraction

• For azoospermic males, search for sperm by a reproductive urologist in the OR,

under anesthesia, through testicular biopsy; used for in vitro fertilization

Donor sperm

• Obtained from a sperm bank; used for intrauterine insemination

Females

Ovarian stimulation

• For females with decreased ovarian reserve, attempt to achieve pregnancy

through ovarian stimulation, egg retrieval, in vitro fertilization, and transfer of

embryos into the uterus

Patient’s frozen embryos or oocytes

• Transfer of thawed embryos (or embryos created from thawed oocytes) into

the uterus

Donor oocytes or embryos

• Oocytes obtained from a younger woman; fertilized with partner or donor sperm

and transferred into the uterus

Cancer and fertility

• Fertile Hope/LIVESTRONG (www.fertilehope.org)

• MyOncofertility (myoncofertility.org) Fertility

• American Society of Reproductive Medicine, ReproductiveFacts (www.reproductivefacts.org)

• InterNational Council on Infertility Information Dissemination (INCIID) (www.inciid.org)

• RESOLVE: The National Infertility Association (www.resolve.org)

• Society for Assisted Reproductive Technology (www.sart.org) Financial assistance (for FP before treatment)

• Fertile Hope (http://www.fertilehope.org/fi nancial-assistance/index.cfm) Adoption

• Adoption.com (www.adoption.com)

• Adoption.org (www.adoption.org)

• Adoptive Families (www.adoptivefamilies.com)

• Adoptive Parents Committee (adoptiveparents.org)

• Yahoo! Groups: Adoption after Cancer (groups.yahoo.com)

FP, fertility preservation.

Trang 20

22 Dolmans MM, Demylle D, Martinez-Madrid B, et al Effi cacy of

in vitro fertilization after chemotherapy Fertil Steril 2005;83(4):

24 Broekmans FJ A systematic review of tests predicting ovarian reserve

and IVF outcome Hum Reprod Update 2006;12(6):685–718.

19 Agarwal SK, Chang RJ Fertility management for women with cancer

Cancer Treat Res 2007;138:15–27.

20 Grifo JA, Noyes N Delivery rate using cryopreserved oocytes is

comparable to conventional in vitro fertilization using fresh oocytes:

potential fertility preservation for female cancer patients Fertil Steril

2010;93(2):391–396.

21 Letourneau JM, Melisko ME, Cedars MI, et al A changing perspective:

improving access to fertility preservation Nat Rev Clin Oncol 2011;

8(1):56–60.

Trang 21

Quality of life issues are exceedingly important in caring

for cancer survivors, and sexual dysfunction is one of the

signifi cant challenges faced by this population Effectively

addressing sexual dysfunction can be diffi cult given the varied

etiologies, multifactorial nature of the disorder, and the

com-fort level of the clinician in addressing it It is important for

primary care providers to address this topic with cancer

survi-vors to improve their quality of life The National Health and

KEY POINTS

• Male and female survivors at highest risk for

treatment-related sexual dysfunction are those with pelvic tumors,

breast cancer, testicular cancer, or those whose

treat-ments affect hormone levels and pathways mediating

sexual desire and pleasure.

• Primary care clinicians can help direct care by exploring

the extent of sexual dysfunction and basing therapeutic

options on the etiology of dysfunction.

• Testosterone effects are complex and use of standard

replacement for sexual dysfunction needs further

evaluation.

• Women with cancer often experience abrupt or premature

menopause from their treatment, which causes them to

have greater intensity and duration of symptoms such

as hot fl ashes, vaginal dryness, dyspareunia, decreased

libido, and changes in sexual response.

• Treatment options for sexual dysfunction in men

depend on etiology of the problem and concomitant

medical conditions Some possible options include

phosphodiesterase-5 inhibitors, SSRIs, penile

supposi-tories, penile injections (alprostadil or phentolamine),

vacuum pumps, or implantable prostheses.

• Treatment options for sexual dysfunction in women also

depend on etiology of the problem and concomitant

medical conditions Some possible options include

lubricants, moisturizers, counseling/sex therapy, altering

contributing medications, physical therapy for pelvic

fl oor disorders, mechanical devices/vibrators, and local

intravaginal estrogens.

Social Life Survey (NHSLS) defi nes sexual dysfunction as

symptoms or problems associated with (1) desire for sex, (2) arousal diffi culties, (3) inability to achieve climax or ejacula-tion, (4) anxiety about sexual performance, (5) climaxing or ejaculating too rapidly, (6) physical pain during intercourse, and (7) not fi nding sex pleasurable.1 Both cancer and its treat-ment can impact sexual function Survivors at highest risk for treatment-related sexual dysfunction are those with pel-vic tumors and those whose treatment affects the hormonal systems mediating sexual desire and pleasure Emotional dis-tress, relationship confl ict, and having a partner with sexual dysfunction can also increase the risk of sexual dysfunction

in survivors.2

Specifi c cancer types are associated with higher rates of sexual dysfunction Men treated for prostate or testicular cancer have an increased risk of sexual dysfunction Erectile dysfunction (ED) rates among these survivors can be related

to extent of surgery, increased doses of external beam tion, and need for hormonal therapy.3,4 Studies attempting

radia-to modify surgery or radiation therapy for prostate cancer radia-to spare sexual function suggest that 75% to 85% of men treated for localized disease still have long-term problems with ED.5

In addressing survivorship care, primary care clinicians can help direct care by exploring the extent of sexual dysfunction and basing therapeutic options on etiology of dysfunction if this can be determined Factors correlated with better out-come include having more counseling sessions, younger age, absence of depression, and absence of marital confl ict.6 The role of hormonal assessment and treatment for male cancer survivors is not clear Low normal to low levels of testoster-one are common in young men treated with high-dose alkyl-ating agent chemotherapy (e.g., Hodgkin and non-Hodgkin lymphoma) Male cancer survivors with androgen defi ciency report impairment in sexual functioning, but studies of replacement have not consistently demonstrated improve-ment Testosterone effects are complex, and use of standard replacement for sexual dysfunction needs further evalua-tion.7,8 Determining primary tumor type, treatment dose, and common side effects of specifi c treatment modalities can help guide evaluation and management To date, most

of the efforts in improving sexual dysfunction in male vors focus on mechanically restoring erectile rigidity A few studies of outcome in impotence clinics where men were not selected for health or etiology of ED demonstrated that only 30% to 40% of men were sexually active and considered their problem resolved up to 5 years after evaluation despite trying

survi-a mesurvi-an of two tresurvi-atments.9

Trang 22

In women, treatment of cancers that affect the sexual

organs such as breast, endometrial, ovarian, cervical, fallopian

tube, and vulva directly impacts sexual function However,

even cancers that do not directly involve sexual organs can

impact sexual health through side effects of the multi modality

treatment Surgery, chemotherapy, endocrine therapy, and

radiation therapy all can cause body image concerns including

decreased feelings of attractiveness and femininity, alopecia,

scars, and weight changes.10,11 Cancer and its treatment can

also lead to fatigue, neuropathy, decreased libido, change in

physical capacity for sex, hormonal changes, anxiety, stress,

depression, infertility, transient or permanent amenorrhea,

and premature menopause

Menopause in the patient with cancer is different than

natural menopause.12 Estrogen depletion from transient or

permanent ovarian suppression leads to instability of the

hypothalamic thermoregulatory set point and allows changes

in body temperatures and hot fl ushing sensations Women

with cancer often experience abrupt or premature menopause

TABLE 42-1 Vaginal Health Products to

Address Sexual Side Effects in Patients Treated for Cancer

• Safe to use with latex condoms

• Apply to both partners during sexual activity

• Examples: K-Y Jelly, Astroglide, vitamin E, Eros for Women, almond oil, and Liquid Silk

Silicone-based

lubricants

• Longer lasting than water-based lubricants

• Increase comfort with sexual activity and decrease pain with intercourse

• Safe to use with latex condoms

• Apply to both partners during sexual activity

• Cannot be used with silicone sex toys

• Examples: K-Y Intrigue, Eros Body Glide, Wet Platinum Silver

Vaginal

moisturizers

• Suppositories that hydrate vaginal tissue

• Improve dryness, pruritus, elasticity, and irritation

• Not uncommon for patients with cancer to use three to

fi ve times per week

• Take 2 mo to realize full benefi t

• May cause watery discharge

• Examples: Replens, K-Y Aquabeads, vitamin E vaginally

Prescription Products

Intravaginal

estrogens

• Reestrogenize vaginal epithelium

• Effective in improving vaginal dryness and comfort

• May cause transient estradiol elevation

• Controversial in women with breast cancer or hormone receptor-positive cancers; safety unclear

• Examples: Vagifem, Estring, Estrace, and Premarin

Therapeutic Approach

Dilator therapy • Mechanically stretches vaginal tissue

• Use to decrease pain with intercourse or gynecologic exams

• Use to prevent or treat vaginal stenosis/adhesions

• Dilators usually come in a set of increasing size

• Help to reduce anxiety about pain and increases confi dence

• Use for 5–10 min several times per week

Pelvic fl oor exercises

• Stretch and relax pelvic fl oor muscles

• Improve control and strength of pelvic muscles

• Use to decrease pain with intercourse or gynecologic exams

• May promote circulation and pelvic blood fl ow

• Daily use recommended

Increase blood fl ow

to pelvic

fl oor

• May promote circulation and arousal response

• May have rehabilitative effects by drawing oxygenated blood

• Methods include pelvic fl oor exercises, vibrators, and self-stimulation

TABLE 42-2 Sexual Health Strategies to Address

Pain and Promote Pelvic Floor Health

in Women Treated for Cancer

from their treatment, which causes them to have greater sity and duration of symptoms such as hot fl ashes, vaginal dryness, dyspareunia, decreased libido, and changes in sexual response.10,11 These symptoms have been shown to negatively impact quality of life Even in women already in menopause, treatment can have signifi cant sexual health effects.13

inten-Changes in sexual health often cause distress When tress is high, libido often declines A decreased libido may cause confusion and embarrassment Many women and men are not cognizant that their sexual problems are related to their treatment Available treatments should be discussed with patients, and, for women, some possibilities are lubri-cants, moisturizers, counseling/sex therapy, altering contrib-uting medications, physical therapy for pelvic fl oor disorders, mechanical devices/vibrators, and local intravaginal estrogens (Tables 42-1 and 42-2).14–17 There are currently no U.S Food and Drug Administration (FDA)–approved medications for decreased libido, arousal, or orgasmic diffi culties in women

dis-However, these are areas of active drug development by maceutical companies Men experiencing sexual dysfunction have a few options for treatment depending on etiology and concomitant medical conditions (Table 42-3).18–19 Exploration

phar-of sexual dysfunction and referral to appropriate specialists for treatment can improve quality of life for survivors

Sexuality in patients with cancer is understudied, and a better understanding of the impact of specifi c treatments on sexual function is needed to appropriately counsel patients about the relative morbidity of cancer treatment strategies

Additional research is warranted to improve prevention, nosis, and treatment of sexual concerns throughout cancer treatment and survivorship Safe and effective interventions

diag-to ameliorate sexual dysfunction in survivors are needed diag-to improve quality of life Because primary care clinicians are often the fi rst level of interaction with the medical community,

it is important that they address this topic with survivors

Trang 23

Ch a p t e r 4 2 / S ex u a l D y s f u n c t i o n 259

Phosphodiesterase-5

inhibitors

• Sildenafi l, vardenafi l, tadalafi l

• Allows accumulation of cyclic GMP within the penis

• 100 mg dose effective in 75% of men

• Contraindicated if patient is also using nitrates

• Taken 1 h before sexual activity and effective for

up to 4 h

SSRI • Inhibits serotonin reuptake by neurons

• May help patients with premature ejaculation

• Effective dose is dependent on specifi c drug.

Penile suppository • Alprostadil is prostaglandin E 1

• Causes smooth muscle relaxation in corpus cavernosum

• Delivered in gel formulation into meatus of penis

• Can be used twice daily

• Inserted up to 10 min prior to sexual activity and effective for 1 h

Penile injection

(alprostadil)

• Prostaglandin E 1 injected into base of penis

• Effective in 50%–85% of patients

• Priapism is an uncommon side effect.

• Injected 10–20 min prior to sexual activity and effective for up to 1 h

TABLE 42-3 Treatment Options for Male Sexual Dysfunction

Penile injection (phentolamine)

• Causes relaxation of penile vascular smooth muscle

• Injected 10–20 min before sexual activity

• Requires stimulation to have erection

Vacuum pump • Draws blood into penile cavernosae

• Tourniquet at base holds blood in penis.

• Infl ated before sexual activity and effective until elastic ring at base is removed

• Erection not to be maintained more than 1 h

Infl atable penile implants

• Offered to patients unresponsive to medical therapy

• Surgically implanted

• Provides reliable long-term erectile function

• High rate of satisfaction among patients

• Available in two or three piece models

• Autoinfl ation can occur with abdominal straining.

• Risk of infection with implanted device

Noninfl atable penile implants

• Semirigid surgically implanted rod

• Permanent erection

• Rod is malleable to allow manipulation by patient.

• Used much less frequently than infl atable device

• May be a good option for older men with limited mental or manual dexterity

GMP, guanosine monophosphate; SSRI, selective serotonin reuptake inhibitor.

References

1 Laumann EO, Paik A, Rosen RC Sexual dysfunction in the United

States Prevalence and predictors JAMA 1999;281:537–544.

2 Nicolosi A, Laumann EO, Glasser DB, et al Global Study of Sexual

Attitudes and Behaviors Investigators’ Group Sexual behavior and

sexual dysfunction after age 40: the global study of sexual attitudes and

behaviors Urology 2004;64:991–997.

3 Hollenbeck BK, Dunn RL, Wei JT, et al Determinants of long-term

sex-ual health outcome after radical prostatectomy measured by a validated

instrument J Urol 2003;169:1453–1457.

4 Jonker-Pool G, Van de Wile HBM, Hoekstra HJ, et al Sexual

function-ing after treatment for testicular cancer: review and meta-analysis of 36

empirical studies between 1975–2000 Arch Sex Behav 2001;30:55–74.

5 Steineck G, Helgesen F, Adolfsson J, et al Quality of life after radical

prostatectomy or watchful waiting N Eng J Med 2002;347:790–796.

6 Schover LS, Evans RB, von Eschenbach AC Sexual rehabilitation in a

cancer center: diagnosis and outcome in 384 consultations Arch Sex Beh

1987;16:445–461.

7 Greenfi eld DM, Walters SJ, Coleman RE, et al Quality of life,

self-esteem, fatigue, and sexual function in young men after cancer Cancer

2010;116:1592–1601.

8 Howell SJ, Radford JA, Adams JE, et al Randomized placebo-

controlled trial of testosterone replacement in men with mild Leydig

cell insuffi ciency following cytotoxic chemotherapy Clin Endocrinol

inhibitors Breast Cancer Res Treat 2010.

12 Ganz PA, Greendale GA, Petersen L, et al Managing menopausal toms in breast cancer survivors: results of a randomized controlled trial

symp-J Natl Cancer Inst 2000;92:1054–1064.

13 Smith IE, Dowsett M Aromatase inhibitors in breast cancer N Engl J Med 2003;348:2431–2442.

14 Mac Bride M, Rhodes D, Shuster L Vulvovaginal atrophy Mayo Clin Proc 2010;85(1):8794.

15 Harris G, Markowski M Successful treatment of orgasmic dysfunction using

specialized physical therapy: a case report J Reprod Med 2009;54:520–522.

16 Rosenbaum T, Owens A The role of pelvic fl oor physical therapy in the treatment of pelvic and genital pain-related sexual dysfunction (CME)

pharmaco-the American College of Physicians Ann Intern Med 2009;151:639.

19 Montague DK, Jarow JP, Broderick GA, et al Chapter 1: the

manage-ment of erectile dysfunction: an AUA update J Urol 2005;174:230.

Trang 24

Endocrinopathies 43

THYROID GLAND DISORDERS

Thyroid gland disorders following cancer treatment are extremely common; a study of 5-year survivors of Hodgkin lymphoma found a cumulative incidence of thyroid chronic conditions exceeding 50% by 30 years from diagnosis (Fig 43-1).5 Radiation therapy to the thyroid gland itself, including craniospinal irradiation (doses ⱖ15 Gy), may not

only lead to central or primary hypothyroidism but can also cause hyperthyroidism (doses ⱖ35 Gy), thyroiditis, or mul-

tinodular goiter Primary hypothyroidism can also be caused

by cytokine treatment or interleukin-based immunotherapy

Tyrosine kinase inhibitors, such as sunitinib and sorafenib, have also been frequently associated with primary hypothy-roidism Thyroid neoplasms, both benign and malignant, are frequently seen following radiation to the gland Children treated prior to the age of 10 years and doses of 20 to 29 Gy

to the thyroid gland are the highest risk groups for these tumors.6,7

HYPOTHALAMIC–PITUITARY DISORDERS

Exposure to high doses of radiation therapy or surgery in the vicinity of HPA places survivors of cancer at risk for multiple hormone defi ciencies, including thyroid-stimulating hormone (TSH), growth hormone (GH), adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and gonadotropin (luteinizing hormone [LH]/follicle-stimulating hormone [FSH]) defi ciencies Patients treated with cranial irradiation are at risk for other endocrinopathies such as hyperprolac-tinemia and central precocious puberty as well

Growth Hormone Defi ciency

GH defi ciency (GHD) is the most common thy seen in survivors of cancer following cranial irradiation,

endocrinopa-KEY POINTS

• Survivors of cancer are at risk for the development of a

wide range of endocrine health conditions as a result of

prior cancer therapies, particularly radiation therapy or

high-dose alkylating agents.

• Hypothalamic–pituitary dysfunction is a dose- and

time-dependent specifi c late effect following cranial irradiation.

• Continued lifelong surveillance is required in both children

and adults for the development of endocrine dysfunction.

• Referral to an endocrinologist is recommended for

management of hormonal issues.

INTRODUCTION

With improvements in cancer detection and treatment,

the population of survivors of cancer in the United States

is growing Unfortunately, exposure to cancer therapies

including surgery, chemotherapy, and radiation can lead to

persistent or late-occurring health outcomes collectively

termed “late effects.” Although endocrine disorders among

survivors of childhood cancers have been well described, the

adult survivorship literature in this area is limited

Nonethe-less, it is important for the adult primary care clinician to

have a basic understanding of common endocrine

complica-tions among survivors In this chapter, we will touch briefl y

on three common cancer treatment–related endocrinopathies:

disorders of the gonads, thyroid, and hypothalamic–pituitary

axis (HPA) as well as the metabolic syndrome Table 43-1

outlines common cancer treatments and their

endocrine-related late effects For detailed clinical guidelines pertaining

to survivors of childhood cancer, the reader is directed to the

Children’s Oncology Group (COG) recommendations

regard-ing cancer-related exposures and potential late effects, which

are publically available at www.survivorshipguidelines.org

GONADAL DYSFUNCTION

Gonadal dysfunction is likely to be the most common late effect

of cancer therapy.1 A functioning gonadal system requires intact

hypothalamus, pituitary, and gonads Therefore, damage to any

part of the system may result in dysfunction Among males,

pri-mary Leydig or germ cell dysfunction can result from alkylating

Trang 25

C h a p t e r 4 3 / E n d o c r i n o p a t h i e s 261

particularly with doses ⱖ18 Gy to the HPA GHD following

irradiation occurs in a dose- and time-related fashion, with risk

increasing with higher doses of radiation and longer interval

from treatment.7 Other risk factors for GHD include younger

age at exposure and female sex GHD should be suspected in

patients with decreased growth velocity over a 6-month period

or a drop in two percentiles on standardized growth curves.8

Adults with GHD often experience increased adiposity as well

as decreased lean mass, strength, bone density, and quality of

life.9 Referral to an endocrinologist should be made for both

children and adults considering GH replacement therapy

Gonadotropin Defi ciency and Precocious Puberty

Survivors who have been treated with cranial radiation are

at risk for central precocious puberty because of premature

activation of the hypothalamic-pituitary-gonadal axis, puberty with accelerated progression, and delayed or arrested puberty because of complete or partial gonadotropin defi ciency resulting in hypogonadotropic hypogonadism.10 Gonadotropin defi ciency in adults is associated with infertility and sexual dysfunction Estrogen and testosterone defi ciencies may be treated with hormone replacement preparations

Thyrotropin Defi ciencyRadiation therapy to the HPA (typically in doses ⱖ30 Gy may

result in TSH defi ciency) Although TSH defi ciency is easily treated with thyroid hormone replacement, clinicians must be careful to follow free thyroxine (T4) levels, not TSH

Other Hormonal DerangementsAdrenal insuffi ciency resulting from loss of ACTH secretion is

a relatively rare occurrence in survivors of cancer, but it may be seen in patients treated with surgery in the region of the HPA

or high-dose radiation (HPA doses ⱖ30 Gy).7,11 Clinical festations include fatigue, weakness, nausea, vomiting, diar-rhea, hypotension, and temperature instability Treatment is with lifelong glucocorticoid replacement therapy Patients who receive very high doses of cranial radiation with HPA doses

mani-⬎40 to 50 Gy may experience elevated levels of prolactin

(PRL) Radiation-induced hyperpro lactinemia is often cally silent, but it can cause pubertal delay in children, galac-torrhea or amenorrhea in women, and decreased libido and impotence in men.12 Treatment is with dopamine agonists, which lead to inhibition of PRL secretion and synthesis

clini-METABOLIC SYNDROME

The metabolic syndrome is a cluster of cardiovascular risk factors including hypertension, dyslipidemia, and central or visceral adiposity associated with an increased risk for the development of type 2 diabetes and atherosclerotic disease

Potential Late

Effect Cancer Therapy

Gonadal dysfunction • Alkylating agents

Osteoporosis • Methotrexate

• Glucocorticoids

• Cranial radiotherapy Diabetes mellitus • Cranial radiotherapy

• Abdominal irradiation and total body irradiation Thyroid dysfunction • Radiotherapy to neck or scatter

• Total body irradiation

• Cytokines and immune therapy

• Tyrosine kinase inhibitors LH/FSH defi ciency • Radiation to the hypothalamic–pituitary axis ( ⱖ30 Gy)

TSH defi ciency • Cranial radiotherapy ( ⱖ30 Gy)

ACTH defi ciency • Cranial radiotherapy ( ⱖ30 Gy)

• Injury to the adrenals (surgery, tumoral expansion)

• Glucocorticoids (transient) SIADH (transient) • Cisplatin

• Cyclophosphamide

• Melphalan

• Vinca alkaloids Hyperprolactinemia • Cranial radiotherapy ( ⬎40–50 Gy)

LH, luteinizing hormone; FSH, follicle-stimulating hormone; TSH, thyroid-stimulating hormone;

ACTH, corticotropin; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

TABLE 43-1 Cancer Therapies and Potential

Endocrine Late Effects

FIGURE 43-1. Cumulative incidence of nonneoplastic chronic conditions in 5-year survivors of childhood Hodgkin lymphoma (Reprinted from Castellino SM, Geiger

AM, Mertens AC, et al Morbidity and mortality in long-term survivors of childhood

Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study Blood 2011:

1806–1816, with permission.)

Years Since Diagnosis

0 0 10.0 20.0 30.0 40.0 50.0 60.0

Thyroid Chronic Condition Cardiac Chronic Condition Pulmonary Chronic Condition

Trang 26

References

1 Schmeigelow M Endocrinological late effects following radiotherapy

and chemotherapy of childhood brain tumours Dan Med Bull 2006;53:

326–341.

2 Chemaitilly W, Mertens AC, Mitby P, et al Acute ovarian failure

in the Childhood Cancer Survivor Study J Clin Endocrinol Metab

2006;91:1723–1728.

3 Sklar CA, Mertens AC, Mitby P, et al Premature menopause in survivors

of childhood cancer: a report from the Childhood Cancer Survivor Study

J Nat Cancer Inst 2006;98:890–896.

4 Walshe JM, Denduluri N, Swain SM Amenorrhea in premenopausal

women after adjuvant chemotherapy for breast cancer J Clin Oncol

2006;24:5769–5779.

5 Castellino SM, Geiger AM, Mertens AC, et al Morbidity and mortality

in long-term survivors of childhood Hodgkin lymphoma: a report from

the Childhood Cancer Survivor Study Blood 2011:1806–1816.

6 Sklar CA, Whitton J, Mertens AC, et al Abnormalities of the thyroid in

survivors of Hodkgin’s disease: data from the Childhood Cancer Survivor

Study J Clin Endocrinol Metab 2000;85:3227–3232.

7 Chemaitilly W, Sklar CA Endocrine complications in long-term

survi-vors of childhood cancer Endocr Relat Cancer 2010;17(3):R141–R159.

8 Nandagopal R, Laverdière C, Mulrooney D, et al Endocrine late effects

of childhood cancer therapy: a report from the Children’s Oncology

Group Horm Res 2008;69(2):65–74.

9 Link K, Moëll C, Garwicz S, et al Growth hormone defi ciency dicts cardiovascular risk in young adults treated for acute lympho-

pre-blastic leukemia in childhood J Clin Endocrinol Metab 2004;89(10):

5003–5012.

10 Cohen L Endocrine late effects of cancer treatment Endocrinol Metab Clin North Am 2005;34(3):769–89, xi.

11 Patterson BC, Truxillo L, Wasilewski-Masker K, et al Adrenal function

testing in pediatric cancer survivors Pediatr Blood Cancer 2009;53(7):

1302–1307.

12 Darzy KH Radiation-induced hypopituitarism after cancer therapy:

who, how and when to test Nat Clin Pract Endocrinol Metab 2009;5(2):

88–99.

13 Baker KS, Chow E, Steinberger J Metabolic syndrome and

cardiovas-cular risk in survivors after hematopoietic cell transplantation Bone Marrow Transplant 2012;47(5):619–625.

14 de Haas EC, Oosting SF, Lefrandt JD, et al The metabolic syndrome in

cancer survivors Lancet Oncol 2010;11(2):193–203.

In studies of survivors of childhood cancer, increased

preva-lence of the metabolic syndrome has been observed in

sur-vivors of hematologic malignancies treated with cranial or

total body irradiation,13 patients with brain tumor treated with

cranial radiotherapy, and those with GHD.14 Higher

preva-lence of the metabolic syndrome has also been reported in

patients with adult-onset hematologic malignancies as well

as prostate and testicular cancers Treatment primarily

con-sists of lifestyle changes such as smoking cessation, increased

physical activity, and dietary modifi cation as well as drug

therapy when indicated

CONCLUSION

Endocrinopathies remain a well-recognized and frequently encountered complication of cancer therapies affecting the thy-roid, gonads, hypothalamus, pituitary, and pancreas Although certain late effects may develop early after treatment, others may not become apparent for many years, thus warranting life-long careful surveillance Awareness of the potential endocrine sequelae of cancer therapies allows for the timely recognition and treatment in those at risk, thereby reducing morbidity and improving quality of life in all survivors of cancer

Trang 27

44CHAPTER

KEY POINTS

• Cancer-associated cognitive change is an emerging

phenomenon demonstrated in multiple well-designed

trials.

• Cognitive impairment may become clinically evident

before, during, and after cancer therapy.

• In addition to chemotherapy, exposure to other cancer

treatments can contribute to cognitive change.

• Cognitive dysfunction is generally not progressive but

may persist for many years after therapy.

• Rehabilitative strategies and medication management

demonstrate promise in improving both function and

quality of life for cancer survivors who encounter this

condition.

Neurocognitive Effects of Cancer and Its Therapy

in prevalence rates refl ects differences in study design and methodology and heterogeneity of cancer and cancer treatments Using even very conservative approximations of prevalence of cognitive impairment would lead one to esti-mate that more than a million cancer survivors are currently living with cognitive impairment related to cancer treatment Longitudinal studies, undertaken primarily among popula-tions with breast cancer, demonstrate that the prevalence

of cognitive impairment is highest during and immediately following treatment Wefel et al.9 suggest that about half of patients who experience acute cognitive changes will recover function by 1 year after completion of cancer therapy How-ever, impairments may not emerge until after the completion

of treatment, suggesting a late neurotoxicity that results in a delayed cognitive dysfunction.10 Although negative results have been reported, the predominance of evidence supports the assertion that cognitive change is experienced by a sub-stantial proportion of patients treated for cancer Population-based studies confi rm that impairments for some individuals persist long into survivorship, impact functional abilities, and quality of life.11,12 Studies elucidating risk factors for persis-tent cognitive dysfunction are needed

Cognitive change following exposure to cranial irradiation

is a distinct form of cancer-associated cognitive dysfunction that is well described in the literature Children exposed to cranial radiation are at particular risk for impairment, but the condition is commonly seen in adults Cognitive change may

be acute (within 2 weeks of radiation exposure), early-delayed encephalopathy (occurs within 1 to 6 months of exposure), or late-delayed encephalopathy (months to years after exposure) Although acute and early-delayed encephalopathies are self-limited and reversible, late-delayed encephalopathy is progressive and irreversible.13

THE PATIENT EXPERIENCE

Common cognitive changes described include challenges with slowed thinking, short-term memory, word fi nding, multitasking, decision making, completion of tasks, and

Neurocognitive dysfunction associated with cancer and

can-cer treatment is commonly described as “chemo brain” by

patients who experience a subjective perception of cognitive

impairment during and after cancer treatment This

colloqui-alism is a misnomer, however, because studies have

demon-strated objective cognitive impairment in patients both prior to

treatment and following cancer treatments that did not include

chemotherapy (e.g., endocrine therapy for breast cancer and

hormone ablation therapy for prostate cancer, radiation of

central nervous system disease) Studies have only begun to

characterize and measure this phenomenon, and the current

state of the research in this area is nascent; however, patients

who present in the primary care setting benefi t from a careful

evaluation and management of their cognitive concerns

INCIDENCE AND NATURAL HISTORY

Cancer-associated cognitive change has been reported in

17% to 75% of patients in various studies.1–8 This variation

Elizabeth A Kvale, MD • Tim Ahles, PhD • Kevin C Oeffinger, MD

Trang 28

Clinicians should weigh factors such as disease type and stage in considering imaging studies In brain cancer survi-vors, cognitive concerns may be the fi rst sign of recurrence

For cancers that frequently metastasize to brain (e.g., lung cancer), cognitive concerns may warrant brain imaging The more common situation, however, is a patient with early-stage breast cancer who presents fairly shortly after the completion of treatment where imaging studies contribute little to the evaluation of a complaint of cognitive dysfunc-tion in the absence of focal neurologic fi ndings or persistent headache

Neuropsychological testing can clarify the diagnosis of neurocognitive dysfunction associated with cancer Many patients fi nd the testing validating, although it may be neces-sary to explain that the testing is “normed” against popula-tion-based means so that a result of “normal” does not mean that they are not experiencing impairment, especially if they were “above average” prior to exposure Neuropsychiatric evaluation provides focused assessment of defi cits within spe-cifi c cognitive domains The pattern of defi cits that emerges will allow the physician, working collaboratively with the neuropsychologist, to discriminate cancer-associated neuro-cognitive dysfunction from progressive dementing illnesses

in older patients Neuropsychological evaluation also vides an assessment of patients’ ability to resume their previ-ous employment or need for workplace accommodations and can be very helpful in instances where patients are unable to resume employment in their previous occupation Formal test-ing also guides rehabilitative and coping approaches by help-ing patients and their physicians gain insight into the activities that are most likely to be problematic and to develop manage-ment strategies Figure 44-1 presents an algorithm to guide the evaluation of a patient presenting with cognitive complaints associated with cancer therapy

pro-A sudden acute confusion or decline in cognitive function

is not consistent with cancer-associated neurocognitive function Patients presenting with acute confusion should be appropriately evaluated, including chemistries and imaging studies

dys-CONSIDERATION OF OTHER FACTORS THAT CONTRIBUTE TO COGNITIVE ISSUES

Several factors may contribute to the cognitive dysfunction experienced by chemotherapy-treated patients with cancer

Evaluation for potentially reversible contributing factors is important Depression is known to impact cognitive function

in older adults17,18 and can be effectively managed with cation, talk therapy, or a combination Screening for factors such as substance abuse, long-standing alcohol use, vitamin defi ciency, and thyroid dysfunction helps to rule out reversible factors The current literature also indicates that comorbidities such as diabetes, vascular disease, and epilepsy have a signifi -cant impact on cognitive function, particularly among older patients.19–23 The use of medications to manage comorbidi-ties or symptoms may contribute to symptoms of cognitive impairment

medi-organization Studies that include neuropsychological

test-ing most commonly demonstrate diffi culty with cognitive

speed of processing, reduced learning effi ciency and

mem-ory retrieval, verbal function, and spatial reasoning.14

Inter-estingly, several studies found that self-report of cognitive

problems do not correlate with performance on

neuropsycho-logical tests but do correlate with measures of depression,

anxiety, and fatigue.15 This fi nding underscores the

impor-tance of screening for these issues in the primary care clinic

for patients presenting with a complaint of cognitive change

following cancer treatment

EVALUATION OF COGNITIVE COMPLAINTS IN

PATIENTS WITH CANCER AND SURVIVORS

Evaluation of the patient presenting with a complaint related

to cognitive functioning following exposure to cancer and

cancer treatment should focus on

• understanding the nature of the patient’s impairment;

• understanding its impact on his or her functioning;

• evaluating the contribution of other medical conditions,

including depression;

• evaluating the contribution of symptom burden such as

pain, insomnia, or fatigue; and

• reassuring yourself and your patient that symptoms do

not refl ect metastatic disease or a progressive neurologic

disorder

Table 44-1 presents examples of interview questions that

are helpful in developing a history related to the symptom of

cognitive impairment These questions are designed to help

the patient describe the impairment and its impact on his or

her functioning and can give the clinician insight into the

likely defi cits the patient is experiencing and guide

subse-quent workup

• Onset: temporality

• Trajectory over time

• Nature of impairments per patient; clarifying questions may include the

following:

• Do you have diffi culty with attention? Multitasking?

• Do you frequently leave tasks incomplete?

• Do you have diffi culty fi nding words?

• Do you have diffi culty remembering things?

• Do you need to use more prompts such as notes or reminders than you

used to?

• Does it take you longer to think through problems? Does your thinking

seem slower?

• Do you have diffi culty turning left across traffi c?

• How does this impact your function? Job performance?

• What are your biggest concerns about your cognitive function?

• What are your most important goals that relate to your cognitive function?

Table 44-1 Focused History for Complaint

of Cognitive Change Associated with Cancer

Trang 29

Ch a p t e r 4 4 / N e u r o c o g n i t i v e E f f e c t s o f C a n c e r a n d I t s T h e ra py 265

survivors, there is robust evidence for enhanced quality of life and reduction of all-cause mortality rates Structured cognitive behavioral therapy interventions also demonstrate promise, with a recent small study by Ferguson et al.24showing improvement in verbal memory, quality of life, and high patient satisfaction measures

• Pharmacologic strategies—Psychostimulants, including methylphenidate and modafi nil, have been used in the con-text of cancer-associated cognitive change.25 The use of psychostimulant medications for this indication is off label but may be helpful for some individuals, particularly those who experience signifi cant symptoms related to attention

DYSFUNCTION ASSOCIATED WITH CANCER

• Patient education—In many cases, patients are

substan-tially reassured to have their symptoms validated and to

learn that this condition is not progressive Table 44-2

summarizes helpful patient education points

• Behavioral strategies—Behavioral approaches to the

man-agement of cognitive dysfunction should include exercise

in patients for whom that recommendation is appropriate

Although there is limited evidence that physical exercise

will directly improve cognitive functioning among cancer

+

Focal Neurologic Findings?

High risk or known metastatic disease?

Possible progressive neurologic disorder based on age/history?

Impact on work capability, substanial functional, or QOL impairment

Selected management Strategy

Neuropsychiatric Testing

FIGURE 44-1. Algorithm for evaluation of cognitive concerns in cancer survivors Onc/neurosurg, oncology/neurosurgery; QOL, quality of life.

• “Chemo brain” is a real phenomenon demonstrated in clinical studies of varied

populations with cancer.

• A subset of patients experience this, but science doesn’t understand which

people are at greatest risk or why it happens.

• It is not like Alzheimer disease—it won’t get progressively worse It is more

accurate to think of this like a mild brain injury.

• Like other brain injuries, both rehabilitation and learning to cope with changes

are important components to improve function.

Table 44-2 Patient Education Points:

Cancer-Associated Cognitive Change

Medication Dosing Relative Cost

Methylphenidate 5–20 mg dosed morning and noon $

Table 44-3 Psychostimulants Used for

Cancer-Associated Cognitive Dysfunction (Off Label)

Trang 30

13 Taphoorn MJ, Klein M Cognitive defi cits in adult patients with brain

tumours Lancet Neurol 2004;3(3):159–168.

14 Wefel JS, Schagen SB Chemotherapy-related cognitive dysfunction

Curr Neurol Neurosci Rep 2012;12(3):267–275.

15 Schagen SB, Boogerd W, Muller MJ, et al Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with tes-

ticular cancer Acta Oncol 2008;47(1):63–70.

16 Kroenke K, Spitzer RL, Williams JB The PHQ-9: validity of a brief

depression severity measure J Gen Intern Med 2001;16(9):606–613.

17 Baune BT, Suslow T, Engelien A, et al The association between sive mood and cognitive performance in an elderly general population—

depres-the MEMO Study Dement Geriatr Cogn Disord 2006;22(2):142–149.

18 Gotlib IH, Roberts JE, Gilboa E In: Sarason IG, Pierce GR, Sarason BR,

eds Cognitive Interference: Theories, Methods, and Findings Mahwah,

NJ: Lawrence Erlbaum Associates; 1996:347–377.

19 Robbins MA, Elias MF, Elias PK, et al Blood pressure and cognitive function in an African-American and a Caucasian-American sample: the

Maine-Syracuse Study Psychosom Med 2005;67(5):707–714.

20 Scott RD, Kritz-Silverstein D, Barrett-Connor E, et al The association

of non-insulin-dependent diabetes mellitus and cognitive function in an

older cohort J Am Geriatr Soc 1998;46(10):1217–1222.

21 Munshi M, Grande L, Hayes M, et al Cognitive dysfunction is

asso-ciated with poor diabetes control in older adults Diabetes Care 2006;

29(8):1794–1799.

22 Martin RC, Griffi th HR, Faught E, et al Cognitive functioning in

com-munity dwelling older adults with chronic partial epilepsy Epilepsia

2005;46(2):298–303.

23 Kuo HK, Jones RN, Milberg WP, et al Effect of blood pressure and diabetes mellitus on cognitive and physical functions in older adults:

a longitudinal analysis of the advanced cognitive training for

inde-pendent and vital elderly cohort J Am Geriatr Soc 2005;53(7):

breast cancer Support Care Cancer 2008;16(6):577–583.

References

1 Hermelink K, Untch M, Lux MP, et al Cognitive function during

neo-adjuvant chemotherapy for breast cancer: results of a prospective,

multicenter, longitudinal study Cancer 2007;109(9):1905–1913.

2 Schagen SB, van Dam FS, Muller MJ, et al Cognitive defi cits after

postoperative adjuvant chemotherapy for breast carcinoma Cancer

1999;85(3):640–650.

3 Tchen N, Juffs HG, Downie FP, et al Cognitive function, fatigue, and

menopausal symptoms in women receiving adjuvant chemotherapy for

breast cancer J Clin Oncol 2003;21(22):4175–4183.

4 van Dam FS, Schagen SB, Muller MJ, et al Impairment of cognitive

function in women receiving adjuvant treatment for high-risk breast

cancer: high-dose versus standard-dose chemotherapy J Natl Cancer

Inst 1998;90(3):210–218.

5 Wieneke M, Dienst E Neuropsychological assessment of cognitive

functioning following chemotherapy for breast cancer Psychooncology

1995;4:61–66.

6 Ahles TA, Saykin AJ, Furstenberg CT, et al Neuropsychologic impact

of standard-dose systemic chemotherapy in long-term survivors of breast

cancer and lymphoma J Clin Oncol 2002;20(2):485–493.

7 Jansen CE, Dodd MJ, Miaskowski CA, et al Preliminary results of a

lon-gitudinal study of changes in cognitive function in breast cancer patients

undergoing chemotherapy with doxorubicin and cyclophosphamide

Psychooncology 2008.

8 Stewart A, Collins B, Mackenzie J, et al The cognitive effects of

adju-vant chemotherapy in early stage breast cancer: a prospective study

Psychooncology 2008;17(2):122–130.

9 Wefel JS, Lenzi R, Theriault RL, et al The cognitive sequelae of

standard-dose adjuvant chemotherapy in women with breast

carci-noma: results of a prospective, randomized, longitudinal trial Cancer

2004;100(11):2292–2299.

10 Wefel JS, Saleeba AK, Buzdar AU, et al Acute and late onset cognitive

dysfunction associated with chemotherapy in women with breast cancer

Cancer 2010;116(14):3348–3356.

11 Jean-Pierre P, Winters PC, Ahles TA, et al Prevalence of self-reported

memory problems in adult cancer survivors: a national cross-sectional

study J Oncol Pract 2012;8(1):30–34.

12 Kvale EA, Clay OJ, Ross-Meadows LA, et al Cognitive speed of

pro-cessing and functional declines in older cancer survivors: an analysis of

data from the ACTIVE trial Eur J Cancer Care (Engl) 2009.

Trang 31

Survivors of Childhood Cancer

• Childhood cancer survivors are at increased risk for

serious late effects.

• Many late effects are appropriate for screening and

surveillance programs.

• Primary care clinicians need to be aware of this high-risk

population.

• A cancer treatment summary and care plan is imperative

for optimal care of this high-risk population.

The past decades have seen tremendous scientifi c gains

resulting in improved survival after childhood cancer

Currently, more than 300,000 survivors of childhood cancer

are living in the United States.1,2 Unfortunately, this population

is at increased risk for many serious and life-threatening late

effects Of those treated in the 1970s, 1980s, and 1990s, about

75% will develop a chronic health condition by 40 years of

age; the condition will be severe or life threatening in more

than 40% (Fig 45-1).3

In that setting, it is imperative that adult primary care

clinicians are aware of this high-risk population and have some

knowledge of treatments and late effects For more detailed

clinical guidelines, the reader is directed to the Children’s

Oncology Group (COG) recommendations regarding

cancer-related exposures and potential late effects, which are

publi-cally available at www.survivorshipguidelines.org

CHEMOTHERAPY

Chemotherapy is the backbone of treatment for most pediatric

cancers because of both the attempt to avoid radiation therapy

(RT) in growing children and the fact that many pediatric

cancers spread rapidly and therefore require systemic

treat-ment Here, we will review general categories of chemotherapy

and common late effects (Table 45-1)

RADIATION

RT is necessary for the cure of many pediatric cancers tunately, the developing and growing organs and tissues of children are often sensitive to the effects of RT Late effects following RT may be apparent very early after treatment (e.g., cognitive dysfunction) or years or decades later (e.g., second malignant neoplasms [SMN] or coronary artery disease [CAD]) The incidence and severity of RT-induced late effects are infl uenced by the organs and tissues involved in the radia-tion fi eld, type of radiation administered, daily fractional and cumulative radiation dose, and age at treatment Table 45-2 lists some of the more common or important late effects asso-ciated with brain, neck, chest, and abdomen or pelvis RT

Unfor-Important surveillance recommendations for second nancies include initiation of early breast cancer surveillance in women exposed to chest RT The risk in these women is sig-nifi cantly elevated (15% to 20% of women will develop breast cancer by the age of 45 years).4 Early detection of breast cancer in these women is imperative because early stage is strongly associated with improved survival, and therapeutic options are limited given prior radiation and chemotherapy treatments Thus, the COG and other groups recommend surveillance with annual mammography and breast magnetic resonance imaging (MRI) starting at the age of 25 years or

malig-8 years after the radiation, whichever occurs last Likewise, for elevated risk of colorectal cancer in survivors exposed to

30 Gy abdominal or pelvic radiation or more, the COG mends colonoscopy starting at the age of 35 years or 10 years after radiation, whichever occurs last

recom-SURGERY

The following sections review the complications associated with a few select surgeries used in the management of child-hood cancers

Amputation/Limb-Sparing SurgeriesAmputation/limb-sparing surgeries are used to prevent local recurrences of bone tumors by removal of all gross and

Trang 32

Chemotherapy Class Potential Late Effect(s)

Alkylating agent (e.g.,

cyclophosphamide)

• Gonadal dysfunction

• Acute myeloid leukemia (AML)

• Pulmonary fi brosis and restrictive lung disease

• Bladder and genitourinary disease

• Renal tubular damage (Fanconi syndrome) Anthracycline

(e.g., doxorubicin)

• Cardiomyopathy

Antimetabolite

(e.g., methotrexate)

• Osteopenia and osteoporosis

Bleomycin • Pneumonitis, pulmonary fi brosis, and acute

respiratory distress syndrome (ARDS) Corticosteroid • Osteonecrosis, osteopenia, and osteoporosis

Heavy metal

(e.g., cisplatin)

• Hearing loss and sensory neuropathy

• Chronic kidney disease and tubular dysfunction Epipodophyllotoxin

(e.g., etoposide)

• Treatment-related acute myeloid leukemia (t-AML)

TABLE 45-1 Potential Late Effects Associated

with Chemotherapy Exposure

Grade 1-5

Grade 3-5 0.4

FIGURE 45-1. Cumulative incidence of chronic health conditions among 10,397

adult survivors of childhood cancer Among the survivors of various types of cancer,

the risk of subsequent health conditions was scored according to the Common

Terminology for Adverse Events (version 3) as mild (grade 1), moderate (grade 2),

severe (grade 3), life threatening or disabling (grade 4), or fatal (grade 5) (Data from

Oeffi nger KC, Mertens AC, Sklar CA, et al Chronic health conditions in adult survivors

of childhood cancer N Engl J Med 2006;355[15]:1572–1582.)

microscopic disease Type of procedure, primary tumor site, and patient’s age affect risk of postsurgical complications

Amputation complications include stump prosthetic problems, chronic stump pain, phantom limb pain, and bone overgrowth

Limb-sparing surgeries, which are aesthetically more ing, have more frequently reported complications including nonunion, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, chronic pain, and poor joint movement

appeal-NephrectomyNephrectomy is a mainstay component of treatment for renal tumors (including Wilms tumor) Complications include renal insuffi ciency, hyperfi ltration injury, hypertension, and hydrocele Compensatory hypertrophy of the remaining kidney often occurs after nephrectomy, likely to adapt to increase in glomerular fi ltration capacity Clinicians should be

Exposure Site Potential Late Effect(s)

Any radiation • Skin, bone, soft tissue malignancies Brain, eyes, and ears • Cognitive dysfunction

• Growth hormone defi ciency

• Obesity and the metabolic syndrome

• Central gonadotropic defi ciency (RT doses ⱖ40 Gy)

• Central adrenal defi ciency (RT doses ⱖ40 Gy)

• Renal insuffi ciency

• Hypertension (especially if combined with nephrotoxic chemotherapy)

• Acute ovarian failure or premature menopause

• Oligospermia or azoospermia and Leydig cell dysfunction

• Delayed puberty

• Functional asplenia (RT doses ⱖ40 Gy)

RT, radiation therapy.

TABLE 45-2 Potential Late Effects Associated

with Radiation Therapy Exposure

Trang 33

C h a p t e r 4 5 / S u r v i v o r s o f C h i l d h o o d C a n c e r s 269

be screened with a one-time ferritin level after treatment has ended; iron chelation may be warranted

PSYCHOSOCIAL ASPECTS OF SURVIVORSHIP

Although many cancer survivors report positive psychosocial gain, such as enhanced self-concept,7 most survivors are at risk for psychiatric outcomes, including major depression, anxiety, and posttraumatic stress disorder (PTSD) Isolation

is frequently seen, both during and after treatment, and many adult survivors are unemployed or underemployed.8 Survi-vors of acute lymphoblastic leukemia (ALL) and brain tumors appear to be at highest risk, but no diagnostic group is immune.9Furthermore, lack of insurance coverage can keep this popu-lation from the care they need.10 Ideally, survivors and their families would benefi t from ongoing psychosocial support

SUMMARY

Late effects of therapy for childhood cancer are common and serious Fortunately, many late effects are modifi able Anticipatory risk-based care can reduce the frequency and severity of treatment-related morbidities The primary care clinician is crucial to providing this risk-based care

to survivors A cancer treatment summary and care plan provided to the primary care clinician together with con-tinued communication between the primary care clinician and the cancer center is imperative for optimal care of this high-risk population

References

1 Mariotto AB, Rowland JH, Yabroff KR, et al Long-term survivors of

childhood cancers in the United States Cancer Epidemiol Biomarkers

Prev 2009;18(4):1033–1040.

2 Ries LAG, Harkins D, Krapcho M, et al., eds SEER Cancer Statistics

Review, 1975–2003 http://seer.cancer.gov/csr/1975_2003/ Accessed

September 22, 2010.

3 Oeffi nger KC, Mertens AC, Sklar CA, et al Chronic health conditions

in adult survivors of childhood cancer N Engl J Med 2006;355(15):

1572–1582.

4 Henderson TO, Amsterdam A, Bhatia S, et al Systematic review:

sur-veillance for breast cancer in women treated with chest radiation for

childhood, adolescent, or young adult cancer Ann Intern Med 2010;152:

444–455; W144–W154.

5 Ejstrud P, Kristensen B, Hansen JB, et al Risk and patterns of

bacter-aemia after splenectomy: a population-based study Scand J Infect Dis

2000;32:521–525.

6 Coleman CN, McDougall IR, Dailey MO, et al Functional hyposplenia

after splenic irradiation for Hodgkin’s disease Ann Intern Med

1982;96:44–47.

7 Barakat LP, Alderfer MA, Kazak AE Posttraumatic growth in

adoles-cent survivors of cancer and their mothers and fathers J Pediatr Psychol

2006;31(4):413–419.

8 Pang JW, Friedman DL, Whitton JA, et al Employment status among adult survivors in the Childhood Cancer Survivor Study Pediatr Blood Cancer 2008;50(1):104–110.

9 Lesko LM Surviving hematological malignancies: stress responses and

predicting psychological adjustment Prog Clin Biol Res 1990;352:

423–437.

10 Park ER, Li FP, Liu Y, et al Health insurance coverage in survivors of

childhood cancer: the Childhood Cancer Survivor Study J Clin Oncol

2005;23(36):9187–9197.

cognizant of other treatments that may impair the remaining

kidney, including platinum and alkylator chemotherapy,

abdominal RT, and supportive care medications such as

aminoglycosides, amphotericin, cyclosporine, or nonsteroidal

anti-infl ammatories

Splenectomy

Prior to the 1990s, most patients with Hodgkin lymphoma

were staged with laparotomy, including splenectomy Asplenic

survivors have a 2% to 4% lifetime risk of overwhelming

sepsis, with a 1% to 2% mortality rate.5 Proper education

regarding this risk, appropriate reimmunization, and prompt

medical evaluation during febrile episodes are important

Specifi cally, survivors should be immunized against

pneu-mococcus, meningococcus, and Haemophilus infl uenzae

Survivors who received 40 Gy or more RT to the spleen are

considered functionally asplenic and should also follow these

recommendations.6

BLOOD TRANSFUSIONS

Childhood cancer survivors treated prior to 1993 (when

hepatitis C virus [HCV] screening was implemented in blood

banks) are at increased risk for transfusion-acquired HCV

Recognizing that some survivors are not sure whether they

received blood products during therapy, the COG recommends

that all survivors treated prior to 1993 be screened for HCV

Additionally, survivors who receive multiple transfusions are

at risk for transfusion-related hemochromatosis and should

Trang 34

Survivors of Hematopoietic Cell Transplantation

46

Mark W Yeazel, MD, MPH • Smita Bhatia, MD, MPHCHAPTER

KEY POINTS

• Hematopoietic cell transplantation is an established

thera-peutic option for several hematologic malignancies.

• More than 70% of those who survive the fi rst 2 years after

HCT are expected to become long-term survivors.

• HCT survivors are at increased risk for developing

long-term complications such as endocrinopathies,

musculoskeletal disorders, cardiopulmonary compromise,

and subsequent malignancies.

• The cumulative incidence of a chronic health condition

among HCT survivors is 59% at 10 years after HCT.

• There is a need to understand the key long-term chronic

health conditions that are likely to be encountered in HCT

survivors to identify those at highest risk and screen the

survivors for these complications with the goal of early

detection and reduction in morbidity.

key long-term complications experienced by HCT survivors, identifying those at increased risk and also describes recom-mendations for follow-up

CARDIAC COMPLICATIONS

HCT survivors are at risk for late cardiotoxicity, including cardiomyopathy, congestive heart failure (CHF), valvular dys-function, arrhythmia, and pericarditis Anthracyclines are the main cause of cardiomyopathy and damage the heart in a dose-dependent fashion Female gender, anthracycline dose exceed-ing 250 mg per m2 alone or with chest radiation, and presence

of multiple cardiovascular risk factors increase the risk of CHF after HCT Mediastinal radiation can produce infl am-mation and fi brosis resulting in restrictive cardiomyo pathy and valvular defects Fibrosis can also affect the electrical conduction pathways causing arrhythmias Cerebrovascular disease and coronary artery disease are prevalent after HCT and often occur earlier than would be expected in the general population.11 Presence of multiple cardiovascular risk fac-tors (obesity, dyslipidemia, hypertension, and diabetes) after HCT increases the risk of cardiovascular disease (cerebrovas-cular and coronary artery disease); pre-HCT chest radiation increases the risk of coronary artery disease.12 HCT survivors are at increased risk for developing de novo cardiovascular risk factors such as diabetes and hypertension because of exposure to total body irradiation (TBI) and prolonged immu-nosuppressive therapy after allogeneic HCT; this increased prevalence of cardiovascular risk factors potentially contrib-utes to the risk of cardiovascular disease (CVD).5

PULMONARY COMPLICATIONS

Noninfectious pulmonary complications are frequent after HCT These include bronchiolitis obliterans (BO) and BO with organizing pneumonia (BOOP).13,14

Hematopoietic cell transplantation (HCT) is an established

therapeutic option for several hematologic malignancies

With advances in transplantation strategies, more than 70%

of those who survive the fi rst 2 years after HCT are expected

to become long-term survivors.1–3 However, HCT survivors

are at increased risk for developing long-term complications

such as endocrinopathies, musculoskeletal disorders,

cardio-pulmonary compromise, and subsequent malignancies.4–8 The

cumulative incidence of a chronic health condition among

HCT survivors is 59% at 10 years after HCT; for severe/

life-threatening conditions, the 10-year cumulative incidence

approaches 35%.9 Of note, HCT-related visits decrease with

time from HCT, placing increasing burden on the primary

care clinics (PCCs) to provide ongoing care to the

survi-vors,10 thus emphasizing the need for increased awareness of

the long-term follow-up needs of HCT survivors by health

care providers in the PCCs This chapter summarizes the

Trang 35

Ch a p t e r 4 6 / S u r v i v o r s o f H e m a t o p o i e t i c C e l l Tra n s p l a n t a t i o n 271

Metabolic SyndromeMetabolic syndrome is a cluster of central obesity, dyslip-idemia, hyperglycemia, and hypertension and conveys an increased risk of type 2 diabetes mellitus and cardiovascu-lar disease Disturbances of the hypothalamic–pituitary axis resulting in growth hormone defi ciency and hypogonadism play a role in the development of metabolic syndrome Chemotherapy and radiation can have direct impact on vas-cular endothelium Dyslipidemia, glucose intolerance, and arterial hypertension can result as a consequence of prolonged immunosuppression with cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil (MMF), and corticosteroids Prev-alence data indicate that 34% to 49% of adult survivors of HCT have one or more components of metabolic syndrome.24

Survivors of allogeneic HCT are 3.7 times more likely to report diabetes mellitus and 2.1 times more likely to report hypertension than their siblings.5

Growth ImpairmentGrowth impairment occurs frequently in children after HCT, primarily because of growth hormone defi ciency after cranial radiation or TBI.25 Patient’s age at HCT is a sig-nifi cant factor in predicting adult height Children younger than 10 years of age at HCT are at greatest risk for short stature.26

Gonadal FailureGonadal failure is a frequent endocrine complication after HCT Pubertal disturbances after HCT are caused by radia-tion-related perturbations of the hypothalamic–pituitary axis and/or by chemoradiotherapy-related damage to the gonads The risk of gonadal failure increases with cumulative doses of gonadotoxic therapies Recovery of spermatogenesis occurs more frequently in patients receiving lower doses of cyclo-phosphamide (120 mg per kg) than in those treated with higher doses (200 mg per kg) Ovaries are more vulnerable

to irradiation and chemotherapy than the testes mately 50% of prepubertal girls given fractionated TBI enter puberty spontaneously and achieve menarche at a normal age, whereas almost all female patients who are more than

Approxi-12 years old at HCT have ovarian failure, probably because

of a decreased reserve of primordial follicles.27 High-dose busulfan is a major cause of ovarian failure even when given

in the prepubertal period.28 Irreversibility of ovarian function after HCT in most patients highlights the necessity of timely hormonal replacement therapy to prevent osteoporosis and other complications

MUSCULOSKELETAL COMPLICATIONS

OsteonecrosisOsteonecrosis (ON) is a painful and debilitating condition that develops when the blood supply to the bone is disrupted, usually in areas with terminal circulation The cumulative incidence of ON is 15% at 10 years after unrelated donor HCT Among allogeneic HCT recipients, male sex; presence

of chronic GVHD; and exposure to cyclosporine, macrolide immunosuppressants, prednisone, and MMF render patients

at increased risk

Bronchiolitis Obliterans

BO is characterized by a nonspecifi c infl ammatory injury

affecting the small airways The presentation of BO is

insidi-ous, with a median latency of 1 year after HCT Manifesting

as an obstructive defect in the initial stages, it progresses

to peribronchiolar fi brosis, with emergence of restrictive

changes.15 Patients present with a dry cough, progressive

dyspnea, and wheezing A characteristic mosaic image on

high-resolution computed tomography of the chest is highly

suggestive of BO.16 Criteria used to make a clinical

diagno-sis of BO include (1) forced expiratory volume in the fi rst

second of expiration (FEV1)/forced vital capacity (FVC)

⬍0.7 and FEV1⬍75% of predicted value, (2) evidence of

air trapping or small airway thickening or bronchiectasis on

high-resolution computed tomography, and (3) absence of

respiratory infection.17

Bronchiolitis Obliterans with Organizing Pneumonia

BOOP is a clinicopathologic syndrome involving

bronchi-oles, alveolar ducts, and alveoli BOOP usually presents as

an interstitial pneumonia and occurs usually within the fi rst

12 months after HCT, with a cumulative incidence of less

than 2% The clinical presentation is acute, with sudden onset

of dry cough, dyspnea, and fever The chest X-ray presents

peripheral patchy consolidation, ground glass attenuation, and

nodular opacities The pulmonary function tests demonstrate a

restrictive pattern Defi nitive diagnosis necessitates histologic

confi rmation

BO and BOOP are caused by an alloimmune response of

donor hematopoietic cells against host lung antigens These

patients are typically treated with immunosuppressive agents;

however, there is no strong evidence that any specifi c therapy

is effective in improving long-term outcomes

ENDOCRINE COMPLICATIONS

Endocrine complications are among the most common chronic

health conditions encountered after HCT and include

thy-roid dysfunction, osteoporosis, metabolic syndrome, growth

impairment, and gonadal dysfunction

Thyroid Abnormalities

Thyroid abnormalities primarily include subclinical and

overt hypothyroidism The incidence of compensated

hypo-thyroidism ranges from 25% to 30%, with median latency

of 2 years The incidence of overt hypothyroidism ranges

from 3.4% to 9.0% with a latency of 2.7 years

Hypothy-roidism is directly related to radiation to the thyroid gland

(as part of neck/mediastinal radiation or TBI) Younger age

increases the risk.18

Osteopenia and Osteoporosis

The decreased bone mineral density is caused by the use of

steroids in the treatment of graft-vs-host disease (GVHD,19

the known association of HCT with growth hormone defi

-ciency20 and hypogonadism,21 physical inactivity, and a

diet low in calcium.22 The incidence of osteopenia in adults

is reported to approach 50% at 4 to 6 years after HCT,

whereas the incidence of osteoporosis approaches 20% at

2 years.22,23

Trang 36

Solid TumorsThe risk of solid tumors increases with time from HCT and, for those who survive 10 or more years after HCT,

is reported to be eightfold that of the general population

Radiation is the single most important risk factor These radiogenic cancers have a long latent period, and the risk is frequently high among patients undergoing irradiation at a young age Immunologic alterations predispose patients to squamous cell carcinoma of the buccal cavity, particularly in view of the association with chronic GVHD.34 Types of solid tumors reported in excess among HCT recipients include melanoma, cancers of the oral cavity and salivary glands, brain, liver, uterine cervix, thyroid, breast, bone, and con-nective tissue.8,35

LATE INFECTIONS

Late infections with bacteria, viruses, fungi, and other isms because of persistent immunodefi ciency are most com-mon in patients with chronic GVHD, in cord blood and T-cell depleted allogeneic HCT recipients, and following CD34-selected autologous transplants It is standard practice

organ-to administer prophylaxis for infections caused by varicella

zoster virus (VZV), Pneumocystis jiroveci, and encapsulated bacteria (Neisseria meningitidis, Haemophilus infl uenzae, and Streptococcus pneumoniae) within the fi rst year after

HCT, or even later, in patients with chronic GVHD In tion, vaccinations are recommended in long-term survivors (Table 46-1)

addi-Bacterial InfectionsThe most signifi cant risk factor for late bacterial infec-tions with encapsulated bacteria is chronic GVHD because

of impaired production of opsonizing antibodies Late infections may also be caused by other organisms such as

Staphylococcus species and gram-negative aerobic

bac-teria Patients with chronic GVHD should have antibiotic prophylaxis targeting encapsulated organisms given for as long as immunosuppressive therapy is administered Admin-istration of prophylactic antibiotics for oral procedures should follow the American Heart Association guidelines for endocarditis prophylaxis All HCT recipients should

receive Pneumocystis jiroveci pneumonia (PCP) prophylaxis

for 6 months or as long as immunosuppressive therapy is given for treatment/prevention of chronic GVHD Because

of the high mortality associated with infections with these organisms, prompt administration of antibiotics with broad-spectrum coverage is imperative when infections are fi rst suspected, with appropriate modifi cations upon identifi ca-tion of the infectious organism

Viral InfectionsVZV disease is the most common late viral infection after HCT It is common practice to recommend oral acyclovir prophylaxis to all allogeneic recipients for the fi rst year after HCT and for longer in patients with ongoing chronic GVHD Most late cytomegalovirus (CMV) disease occurs during the fi rst year after HCT but in some cases may occur

up to 3 years after HCT Gastroenteritis and pneumonia are the most common late manifestations of CMV disease Late CMV pneumonia is associated with the highest mortality

VISUAL IMPAIRMENTS

Cataracts

Cataracts are a well-described complication in HCT

survi-vors Among survivors of HCT performed in childhood, the

cumulative incidence of cataracts is 36% at 15 years

post-HCT.29 Cataracts are seen mainly among patients who had

received TBI for conditioning or cranial irradiation prior to

HCT Survivors of allogeneic HCT are more likely to report a

cataract (cumulative incidence of 40% at 15 years) when

com-pared with autologous HCT recipients (cumulative incidence

of 21%) Furthermore, among allogeneic HCT recipients,

those with chronic GVHD are more likely to report a cataract

(cumulative incidence of 46% at 15 years)

SUBSEQUENT MALIGNANT NEOPLASMS

An important and potentially devastating complication of HCT

is the occurrence of subsequent malignant neoplasms (SMNs)

The magnitude of risk of SMNs after HCT ranges from twofold

to 11-fold that of the general population Risk factors include

age at HCT, exposure to chemotherapy and radiation prior to

HCT, use of TBI and high-dose chemotherapy for

myeloabla-tion, infection with viruses such as Epstein-Barr virus (EBV)

and hepatitis B and C viruses (HBV and HCV), immunodefi

-ciency after HCT aggravated by the use of immunosuppressive

drugs for prophylaxis and treatment of GVHD, type of

trans-plantation (autologous vs allogeneic), source of hematopoietic

stem cell, and primary malignancy.30 SMNs are classifi ed into

three distinct groups31: (1) therapy-related myelodysplasia

(t-MDS) and therapy-related acute myeloid leukemia (t-AML),

(2) lymphoma and other lymphoproliferative disorders, and

(3) solid tumors Although secondary leukemia and lymphoma

develop relatively early in the posttransplantation period,

sec-ondary solid tumors have a longer latency

Myelodysplasia and Acute Myeloid Leukemia

The t-MDS/t-AML are the major cause of nonrelapse

mor-tality in patients undergoing autologous HCT for Hodgkin

lymphoma (HL) and non-Hodgkin lymphoma (NHL).1,32 The

cumulative probability of t-MDS/t-AML ranges from 1.1% at

20 months to 24.3% at 43 months after autologous HCT, with

a median latency of 12 to 24 months after HCT Two types of

t-MDS/t-AML are recognized in the World Health

Organiza-tion (WHO) classifi caOrganiza-tion, depending on the causative

thera-peutic exposure: alkylating agent/radiation and topoisomerase

II inhibitor.33 In patients exposed to alkylating agents, t-MDS/

t-AML usually appears 4 to 7 years after exposure There is

a high prevalence of abnormalities involving chromosomes

5 (-5/del[5q]) and 7 (-7/del[7q]) The t-AML secondary to

topoisomerase II inhibitors presents as overt leukemia without

a preceding myelodysplastic phase The latency is brief,

rang-ing from 6 months to 5 years, and is associated with balanced

translocations involving chromosome bands 11q23 or 21q22

The risk of t-MDS/t-AML increases with older age at HCT30;

pretransplantation therapy with alkylating agents,

topoisom-erase II inhibitors (such as etoposide), and radiation therapy32;

use of peripheral blood hematopoietic cells; stem cell

mobili-zation with etoposide; diffi cult stem cell harvests;

condition-ing with TBI; number of cluster of differentiation (CD) 34⫹

cells infused; and a history of multiple transplants.30,32

Trang 37

Continued monitoring and preemptive therapy is useful in

patients at risk for late CMV disease Patients with chronic

GVHD are also at risk for acquisition of respiratory virus

infections such as respiratory syncytial virus and infl uenza

and parainfl uenza viruses Seasonal vaccination of close

contacts with the inactivated vaccine is recommended (see

Table 46-1) Finally, HBV and HCV may result in chronic

hepatitis and cirrhosis

Fungal Infections

Late invasive aspergillosis is most commonly seen in patients

with chronic GVHD and preceding CMV or respiratory virus

infections The outcome of both mold and candidal infections

in the setting of chronic immunosuppression remains poor

Some experts recommend antifungal prophylaxis in patients

receiving chronic or high-dose corticosteroids for chronic

GVHD Sensitive diagnostic tests (Aspergillus galactomannan

assay and polymerase chain reaction) may help in establishing

an early diagnosis

Recommended VaccinationsHCT recipients have declining levels of antibodies to vac-cine-preventable diseases in the fi rst few years after HCT, and hence lose protective immunity if they are not revac-cinated The response of the HCT recipients to vaccina-tion depends on the timing of the vaccine after HCT, the immunogenicity of the vaccine, and the immune status of the recipients at the time of the vaccinations Inactivated

or subunit vaccines are generally safe in HCT patients, but all live vaccines are contraindicated in the fi rst 2 years after

12 Month Post-HCT 14 Month Post-HCT 18 Month Post-HCT 24 Month Post-HCT

Seasonal infl uenza (inactivated)g,h Seasonal; lifelong administration; start before HCT then resuming ⱖ6 mo after HCT

Seasonal infl uenza (live, nasal) Contraindicated in all stem cell transplant recipients

Measles, mumps, rubella (MMR)i Contraindicated in stem cell transplant recipients with chronic GVHD or

on immunosuppressants

X

Varicellaj Limited data, optional in pediatric HCT recipients; not for adults

a Patients who are immunocompetent (off all immunosuppressive medication) and do not have chronic GVHD should be immunized according to the schedule outlined previously.

b Post-hematopoietic cell transplantation (HCT) patients should be viewed as never vaccinated and receive full doses of toxoids; their diphtheria/tetanus toxoid (DT) vaccine should include full

dose acellular pertussis toxoid if possible Diphtheria, tetanus, and pertussis (DTaP) vaccine should be administered to children ⬍7 years of age Tetanus, diphtheria, and pertussis (Tdap) is

recommended for patients ⬎7 years of age Tdap should replace a single dose of Td as booster for adults ⱖ19 years for those who have not received a dose of Tdap for ⱖ10 years Then boost

with Td every 10 years.

c Oral polio vaccine is no longer recommended for routine immunization in the United States.

d Hepatitis A: Give with hepatitis B in a combination vaccine hep A/B at hepatitis B schedule in ⱖ18 years For people 1 to 18 years old, single antigen hepatitis A vaccine formulations should be

administered in a two-dose schedule at 12 and 24 months post-HCT.

e HPV is recommended in all females at ages 11 to 12 years (range 9 to 26 years) who have not completed the series.

f Pneumococcal: all ages: PCV (pneumococcal conjugated vaccine) total three doses 1 month apart A fourth dose with PPSV (pneumococcal polysaccharide) 7 months after the last PCV may be given to

broaden immune response In patients with chronic GVHD who may have poor response to PPSV; fourth dose with PCV may be considered instead Lifelong prophylactic penicillin is recommended for

splenectomized patients For patients with penicillin allergies, erythromycin or clarithromycin may be used.

g Meningococcal: indicated in anatomic or functional asplenia, terminal component defi ciencies, travel to endemic areas, and all college students living in dorm rooms who have not been previously

immunized.

h Infl uenza: It is strongly recommended that all household members of an HCT recipient receive the infl uenza vaccine on an annual basis HCT recipients themselves should also receive this vaccination

on an annual basis beginning before HCT and then resuming at least 6 months post-HCT For children ⬍9 years, fi rst year post-HCT, two doses are recommended to be administered 1 month apart and

then one dose annually thereafter.

i MMR: Contraindicated for patients ⱕ24 months post-HCT, with chronic GVHD, or on immunosuppressants Not generally recommended for all transplant recipients, although should generally be

administered to children.

j Varicella vaccine: Not for adults Limited data on safety and effi cacy May be considered optional in pediatric patients and only if ⬎24 months post-HCT, no active GVHD, and not on steroids or

immunosuppressants.

GVHD, graft versus host disease.

TABLE 46-1 A Suggested Immunization Schedule for Hematopoietic Cell Transplantation (HCT) Recipientsa

Trang 38

to survivors 2 or more years after therapy is completed.37Table 46-2 summarizes the most commonly observed adverse outcomes after HCT, the therapeutic exposures that are associated with these complications, and recommenda-tions distilled from the two sources cited previously in terms

of the recommended evaluations and counseling for HCT survivors

HCT or in patients with chronic GVHD Table 46-1 details a

suggested immunization schedule for HCT recipients drawn

from the Centers for Disease Control and Prevention (CDC)

guidelines However, there is no data indicating the effi cacy

of these vaccinations in preventing infection, and it cannot

be assumed that the development of antibody titers after

vaccination necessarily correlates with protective immunity

in the HCT recipient

RECOMMENDED SCREENING

Two major groups have developed guidelines for the

follow-up of HCT survivors The Center for International Blood and

Marrow Transplantation Research (CIBMTR), European

Group for Blood and Marrow Transplantation (EBMT), and

Pre-HCT anthracyclines Echocardiographic evaluation every 1–5 y depending on anthracycline dose;

cardiovascular risk factor assessment and counseling; monitor pregnant women closely

Myocardial infarction Pre-HCT radiation to chest Cardiovascular risk factor assessment and counseling

Pulmonary complications Pre-HCT bleomycin, carmustine, radiation to

chest, TBI

CXR and PFT at baseline and as clinically indicated; assess for symptoms such as chronic cough and dyspnea; infl uenza and pneumococcal vaccines; counsel on risk of smoking and secondhand smoke

Hypothyroidism Pre-HCT radiation to neck or mediastinum, TBI TSH and free thyroxine annually

Hypogonadism Pre-HCT radiation to pelvis, l umbar–sacral

spine, and brain; alkylating agents

Males: age-appropriate history and Tanner staging; measure LH, FSH, and testosterone at the age of 14 y or if delay of puberty is suspected.

Females: history and Tanner staging; measure FSH, LH, and estradiol at the age of

13 y, if delay of puberty is suspected, or for irregular menses or amenorrhea.

Short stature Pre-HCT cranial irradiation, TBI, corticosteroids Growth and growth velocity should be measured every 6 mo during childhood.

Osteopenia/osteoporosis Pre-HCT cranial irradiation, TBI, gonadal

radia-tion, corticosteroids

Baseline dual-emission X-ray absorptiometry or quantitative CT scan with repeat as clinically indicated; use of calcium supplements, bisphosphonates, or hormone replacement (in patients with gonadal failure) as clinically indicated

Avascular necrosis Corticosteroids, high-dose radiation to any bone,

History (fatigue, bleeding, easy bruising); dermatologic exam and CBC/differential annually for up to 10 y posttransplant

Solid tumors Pre-HCT radiation and chemotherapies Physical exam for benign or malignant neoplasms annually

Solid tumors Females with radiation ⱖ20 Gy to mantle,

mediastinum, lung, or axillary fi elds

Annual clinical breast exam from puberty to the age of 25 y, then every 6 mo; annual mammogram and MRI 8 y after radiation therapy or at the age of 25 y (whichever

is later) Solid tumors Radiation ⱖ30 Gy to abdomen, pelvis, or spine Colonoscopy every 5 y beginning at the age of 35 y or 10 y after radiation therapy

(whichever is later)

TBI, total body irradiation; CXR, chest X-ray; PFT, pulmonary function test; TSH, thyroid-stimulating hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; CT, computed tomography;

CBC, complete blood count; MRI, magnetic resonance imaging.

TABLE 46-2 Periodic Evaluation of Long-term Survivors of Hematopoietic Cell Transplantation (HCT)

Trang 39

18 Ishiguro H, Yasuda Y, Tomita Y, et al Long-term follow-up of thyroid tion in patients who received bone marrow transplantation during child-

func-hood and adolescence J Clin Endocrinol Metab 2004;89:5981–5986.

19 Ebeling PR, Thomas DM, Erbas B, et al Mechanisms of bone loss lowing allogeneic and autologous hematopoietic stem cell transplanta-

fol-tion J Bone Miner Res 1999;14:341–350.

20 Aisenberg J, Hseih K, Kalaitzoglou G, et al Bone mineral density in

young adult survivors of childhood cancer J Pediatr Hematol Oncol

1998;20:241–245.

21 Schuttle CMS, Beelen DW Bone loss following hematopoietic cell

trans-plantation: a long-term follow-up Blood 2004;103:3635–3643.

22 Schimmer AD, Minden MD, Keating A Osteoporosis after blood and

marrow transplantation: clinical aspects Blood Marrow Transplant

2000;6:175–181.

23 Stern JM, Sullivan KM, Ott SM, et al Bone density loss after allogeneic

HCT: a prospective study Biol Blood Marrow Transplant 2001;7:257–264.

24 Majhail NS, Flowers M, Ness KK, et al High prevalence of metabolic

syn-drome after allogeneic hematopoietic cell transplantation Bone Marrow Transplant 2009;43:49–54.

25 Chemaitilly W, Sklar CA Endocrine complications of hematopoietic cell

transplantation Endocrinol Metab Clin N Am 2007;36:983–998.

26 Sanders JE Growth and development after hematopoietic cell transplant

in children Bone Marrow Transplant 2008;41:223–227.

27 Sanders JE The impact of bone marrow transplant preparative regimens on

subsequent growth and development Semin Hematol 1991;28:244–249.

28 Teinturier C, Hartmann O, Valteau-Couannet D, et al Ovarian function after autologous bone marrow transplantation in childhood: high-dose

busulfan is a major cause of ovarian failure Bone Marrow Transplant

1998;22:989–994.

29 Gurney JG, Ness KK, Rosenthal J, et al Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood: results from the Bone Marrow

Transplant Survivor study Cancer 2006;106:1402–1408.

30 Bhatia S, Ramsay NK, Steinbuch M, et al Malignant neoplasms

follow-ing bone marrow transplantation Blood 1996;87:3633–3639.

31 Witherspoon RP, Fisher LD, Schoch G, et al Secondary cancers after

bone marrow transplantation for leukemia or aplastic anemia N Engl J Med 1989;321:784–789.

32 Krishnan A, Bhatia S, Slovak ML, et al Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors 2000;95:1588–1593.

33 Vardiman JW, Harris NL, Brunning RD The World Health

Organiza-tion (WHO) classifi caOrganiza-tion of the myeloid neoplasms Blood 2002;100:

2292–2302.

34 Leisenring W, Friedman DL, Flowers ME, et al Nonmelanoma skin and

mucosal cancers after hematopoietic cell transplantation J Clin Oncol

2006;24:1119–1126.

35 Curtis RE, Rowlings PA, Deeg HJ, et al Solid cancers after bone marrow

transplantation N Engl J Med 1997;336:897–904.

36 Majhail NS, Rizzo JD, Lee SJ, et al Recommended screening and ventive practices for long-term survivors after hematopoietic cell trans-

pre-plantation Bone Marrow Transplant 2012;47:337–341.

37 The Children’s Oncology Group Long-Term Follow-Up Guidelines for survivors of childhood, adolescent, and young adult cancers Available at http://www.survivorshipguidelines.org/

References

1 Bhatia S, Robison LL, Francisco L, et al Late mortality in survivors

of autologous hematopoietic cell transplantation: report from the Bone

Marrow Transplant Survivor Study Blood 2005;105:4215–4222.

2 Bhatia S, Francisco L, Carter A, et al Late mortality after allogeneic

hematopoietic cell transplantation and functional status of long-term

survivors Report from the Bone Marrow Transplant Survivor Study

Blood 2007;110:3784–3792.

3 Socie G, Stone JV, Wingard JR, et al Long-term survival and late deaths

after allogeneic bone marrow transplantation Late Effects Working

Committee of the International Bone Marrow Transplant Registry

New Engl J Med 1999;341:14–21.

4 Armenian S, Sun CL, Francisco L, et al Late clinical heart failure

(CHF) following hematopoietic cell transplantation J Clin Oncol

2008;26:5537–5543.

5 Baker KS, Ness KK, Steinberger J, et al Diabetes, hypertension and

cardiovascular events in survivors of hematopoietic cell

transplanta-tion: a report from the bone marrow transplant survivor study Blood

2007;109:1765–1772.

6 Brennan BMD, Shalet SM Endocrine late effects after bone marrow

transplant Br J Haematol 2002;118:58–66.

7 Leiper AD Non-endocrine late complications of bone marrow

transplan-tation in childhood: part II Br J Haematol 2002;118:23–43.

8 Rizzo JD, Curtis RE, Socie G, et al Solid cancers after allogeneic

hema-topoietic cell transplantation Blood 2009;113:1175–1183.

9 Sun CL, Francisco L, Kawashima T, et al Prevalence and predictors

of chronic health conditions after hematopoietic cell transplantation:

a report from the Bone Marrow Transplant Survivor Study Blood

2010;116:3129–3139.

10 Shankar S, Carter A, Sun CL, et al Health care utilization by adult

long-term survivors of hematopoietic cell transplant: report from the Bone

Marrow Transplant Survivor Study Cancer Epidemiol Biomarkers Prev

2007;16:834–839.

11 Tichelli A, Bucher C, Rovo A, et al Premature cardiovascular disease

after allogeneic hematopoietic stem-cell transplantation Blood 2007;

110:3463–3471.

12 Armenian SH, Sun CL, Mills G, et al Predictors of late cardiovascular

complications in survivors of hematopoietic cell transplantation Biol

Blood Marrow Transplant 2010;6:1138–1144.

13 Yoshihara S, Yanik G, Cooke KR, et al Bronchiolitis obliterans

syn-drome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP),

and other late-onset non-infectious pulmonary complications following

allogeneic stem cell transplantation Biol Blood Marrow Transplant

2007;13:749–759.

14 Santo Tomas TH, Loberiza FR, Klein JP, et al Risk factors for

bronchi-olitis obliterans in allogeneic hematopoietic stem cell transplantation for

leukemia Chest 2005;128:153–161.

15 Pandya CM, Soubani AO Bronchiolitis obliterans following

hemato-poietic cell transplantation: a clinical update Clin Transplant 2010;24:

291–306.

16 Barkier AA, Van MA, Knoop C, et al Bronchiolitis obliterans

syn-drome in heart-lung transplant recipients: diagnosis with expiratory CT

Radiology 2001;218:533–539.

17 Filipovich AH, Weisdorf D, Pavletic S, et al National Institutes of Health

consensus development project on criteria for clinical trials in chronic

graft versus host disease: I Diagnosis and staging working group report

Biol Blood Marrow Transplant 2005;11:945–956.

Trang 40

47

Sequelae of CancerBriana L Todd, MS • Alton Hart Jr, MD, MPH •

Michael Feuerstein, PhD

KEY POINTS

• Cancer survivors of adult onset cancer can experience

long-term and late psychosocial sequelae due to cancer

and its treatment.

• Currently, many of these psychosocial problems are not

being addressed.

• Simple evidence-based screening and interventions can

take place during an extended offi ce visit.

• There are several resources available to assist primary

care providers and cancer survivors in the management of

psychosocial sequelae.

that there are many unmet psychosocial needs reported by survivors of post-cancer treatment.2 In recent years, can-cer patients are living longer and have been included in the category of those living with a chronic illness How-ever, cancer survivors report higher levels of distress than those with other chronic illnesses.3 Some of the problems contributing to this distress can include cognitive limita-tions, depressive symptoms, anxiety, pain, fatigue, sleep problems, and sexual dysfunction.4 Cancer survivors may also have the expectation that recovery will only require a few months, but in reality, symptoms and changes in func-tion can persist for a lifetime Fortunately, there are tools available that can assist primary care clinicians identify and manage this distress in cancer survivors Also, it is impor-tant to realize that triage to behavioral health providers is not the only option when managing heightened levels of distress in cancer survivors Other providers offer a range

of approaches for distress and the many problems that can trigger it

HOW TO IDENTIFY WHO NEEDS HELP

Cancer survivors report that psychosocial concerns are not adequately addressed in offi ce visits with their physician providers.5 Although asking questions about psychosocial problems does add time to an offi ce visit, there are a few simple procedures that one can follow A discussion with the patient and the use of a brief patient report measure of level and sources of distress can help identify options to manage these psychosocial concerns Primary care clinicians can either use this information to directly assist the patient further identify problem areas and solutions or to play a role in facili-tating necessary referrals to others

Brief Psychosocial ProbeWhat questions might be helpful to ask? Prior to asking ques-tions in this sensitive area, it can be helpful to normalize the types of psychosocial problems (e.g., fears, mood changes, feeling of loss of control) that cancer survivors experience

WHAT ARE THE PSYCHOSOCIAL SEQUELAE

OF CANCER TREATMENT?

Most cancer patients recover following treatment despite

its toxic nature However, a large subset of patients with

adult-onset cancer experiences several psychosocial

prob-lems following treatment The primary care clinician is

in an ideal position to evaluate these problems, manage

them in the offi ce, or, when justifi ed, refer the patient to

an appropriate resource This chapter provides guidance

in addressing these problems In cancer survivors, who are

defi ned in this chapter as being post-primary cancer

treat-ment, psychosocial challenges can range from emotional

and functional problems because of pain to low mood to

diffi culty managing work and family Although over time,

these symptoms tend to decline in severity, they can persist

for many years and impact health, levels of function, and a

sense of well-being

There is a need to proactively evaluate and manage the

psychosocial sequelae of cancer survivors.1 Surveys indicate

The opinions and assertions contained herein are the private views of

the authors and not to be construed as being offi cial or as refl ecting

the views of the Uniformed Services University of the Health

Sciences or the Department of Defense.

Định dạng
Số trang	189
Dung lượng	9,09 MB